Heteromonocyclic compound and use thereof

ABSTRACT

A compound represented by the formula (I): 
     
       
         
         
             
             
         
       
         
         
           
             wherein R1 is an oxo group, ═N—R or the like; a group represented by the formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             is a group represented by the formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             R2 is a group represented by the formula: 
           
         
       
    
     
       
         
         
             
             
         
       
         
         
           
             R3 and R4 are each H, or C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkylamino, di(C1-C6)alkylamino or C1-C6 alkylthio, each of which is optionally substituted; and R5 is H, or C1-C6 alkyl, C2-C6 alkenyl, cyclic group, each of which is optionally substituted, —CO—R8 or —O—R8′, or a salt thereof. The compound of the present invention is useful as a drug for the prophylaxis or treatment of cardiovascular diseases, metabolic diseases and/or central nervous system diseases.

This application is a divisional of U.S. application Ser. No.12/114,048, filed May 2, 2008, which is a continuation-in-part ofapplication Ser. No. 11/943,910, filed Nov. 21, 2007, which claims thebenefit of Japanese patent application No. 2006-317839, filed Nov. 24,2006, and Japanese patent application No. 2007-232106, filed Sep. 6,2007, the contents of which are incorporated in full herein by thisreference.

TECHNICAL FIELD

The present invention relates to a novel heteromonocyclic compoundhaving superior properties as a pharmaceutical agent, a productionmethod thereof and use thereof. More particularly, the present inventionrelates to a heteromonocyclic compound having a particular structure andsuperior pharmacological action such as strong and sustainedantihypertensive action, insulin sensitizing activity and the like, andsuperior property such as crystallinity and stability and the like,which is useful as an agent for the prophylaxis or treatment ofcardiovascular diseases such as hypertension, cardiac disease (cardiachypertrophy, heart failure, myocardial infarction and the like),arteriosclerosis, kidney disease (diabetic nephropathy, chronicglomerulonephritis and the like), stroke and the like; metabolicdiseases such as dyslipidemia, obesity, diabetes and the like; and/orcentral nervous system diseases such as depression, dementia,Alzheimer's disease and the like, or a salt thereof, or a prodrugthereof, a production method thereof, and use thereof and the like.

BACKGROUND OF THE INVENTION

U.S. Pat. No. 5,183,899 (JP-A-3-218371) describes a compound representedby the formula

wherein R is an alkyl group and D is an alkoxy group, a hydroxyl group,a halogen atom or an amino group which may be substituted, or a saltthereof, and that the compound has an angiotensin II receptorantagonistic action and a antihypertensive action and is useful as atherapeutic agent for cardiovascular diseases such as hypertension,cardiac disease, stroke and the like.

U.S. Pat. No. 5,162,326 (JP-A-4-330072) describes a compound representedby the formula

wherein R¹ is hydrogen or a hydrocarbon residue which may besubstituted; R² is hydrogen, halogen, nitro, optionally substitutedamino, formyl or a hydrocarbon residue which may be substituted; R³ is ahydrocarbon residue which may be substituted; R⁴ is hydrogen, halogen ornitro; R⁵ is a residue capable of forming an anion or a residueconvertible into an anion; X is a direct bond or a spacer having oneatomic length and containing an oxygen, nitrogen or sulfur atom; Y is adirect bond or a spacer having atomic length of two or less between thephenylene group and the phenyl group; n is an integer of 1 or 2; or asalt thereof, and that the compound has an angiotensin II receptorantagonistic action and a antihypertensive action and is useful as atherapeutic agent for cardiovascular diseases such as hypertension,cardiac disease, stroke and the like.

U.S. Pat. No. 5,304,565 (JP-A-5-155862) describes a compound representedby the formula

wherein R¹, which may be optionally bound through a hetero atom, is ahydrocarbon residue which may be substituted; R² and R³ which may besame or different, are each independently hydrogen, cyano, nitro,optionally substituted lower alkyl, or a group of the formula —CODwherein D is alkoxy, hydroxy, halogen, or optionally substituted amino,or R² and R³ are taken together to form a benzene ring which may besubstituted; Y is N or CH; Z is bound to a ring nitrogen atom and is agroup having the formula

wherein R⁴ is hydrogen, halogen or nitro, and R⁵ is a residue capable offorming an anion or a residue convertible into an anion; X is a directbond or a spacer having atomic length of two or less between thephenylene group and the phenyl group; n is an integer of 1 or 2; and thedotted line shows that one double bond exists; or a salt thereof, andthe compound has an angiotensin II receptor antagonistic action and aantihypertensive action and is useful as a therapeutic agent forcardiovascular diseases such as hypertension, cardiac disease, strokeand the like.

U.S. Pat. No. 5,243,054 (JP-A-5-271228) describes a compound representedby the formula

wherein R¹ is an optionally substituted hydrocarbon residue which isoptionally bonded through a hetero atom; R² is an optionally substituted5-7 membered heterocyclic residue having, as a group capable ofconstituting the ring, a carbonyl group, a thiocarbonyl group, anoptionally oxidized sulfur atom or a group convertible into them; X is adirect bond or a spacer having an atomic length of two or less betweenthe ring Y and the ring W; W and Y are independently an optionallysubstituted aromatic hydrocarbon residue optionally containing a heteroatom or an optionally substituted heterocyclic residue; n is an integerof 1 or 2; a and b forming the heterocyclic residue are independentlyone or two optionally substituted carbon or hetero atoms; c is anoptionally substituted carbon or hetero atom; and, in the group of theformula

substituents on adjacent two atoms forming the ring are optionallybonded to each other to form a 5-6 membered ring together with the twoatoms forming the ring, or a salt thereof, and that the compound has anangiotensin II receptor antagonistic action, a antihypertensive actionand a central nervous system action and is useful as a therapeutic agentfor cardiovascular diseases such as hypertension, cardiac disease,stroke, kidney diseases, arteriosclerosis and the like, or Alzheimer'sdisease or senile dementia.

U.S. Pat. No. 5,500,427 (JP-A-6-239859) describes a compound representedby the formula

wherein R¹ is an optionally substituted hydrocarbon residue which isoptionally bound through a hetero atom or an optionally substituted acylgroup; R² is an optionally substituted 5-7 membered heterocyclic residuehaving, as a group capable of constituting the ring, carbonyl group,thiocarbonyl group, an optionally oxidized sulfur atom or a groupconvertible into them; Q is CH or N; X is a direct bond or a spacerhaving an atomic length of two or less between the ring Y and the ringW; rings W and Y are each an optionally substituted aromatic hydrocarbonresidue optionally containing a hetero atom or an optionally substitutedheterocyclic residue; n is an integer of 1 or 2; the ring A is anoptionally substituted 5-8 membered cyclic group, and two of is thesubstituents are optionally bound to each other to form a ring, or asalt thereof, and that the compound has an angiotensin II receptorantagonistic action and a antihypertensive action, and is useful as atherapeutic agent for cardiovascular diseases such as hypertension,cardiac disease, kidney diseases (or nephropathy), stroke and the like,or an agent for improving cerebral function.

U.S. Pat. No. 5,496,835 (JP-A-7-070118) describes a compound representedby the formula

wherein the ring A is a 5-10 membered aromatic heterocyclic groupoptionally having, besides R¹ and R², further substituents; R¹ is anoptionally substituted hydrocarbon residue which is optionally bondedthrough a hetero atom; R² is a group capable of liberating proton in aliving body or a group convertible thereinto; R³ is an 5-7 memberedoptionally substituted heterocyclic residue having, as a group capableof constituting the ring, carbonyl group, thiocarbonyl group, anoptionally oxidized sulfur atom or a group convertible into them; Xshows that the ring Y and the ring W are bonded to each other directlyor through a spacer having an atomic length of two or less; the ring Wand the ring Y are each an optionally substituted aromatic hydrocarbonor aromatic heterocyclic residue; and n is an integer of 1 to 3, or asalt thereof, and that compound has an angiotensin II receptorantagonistic action and a antihypertensive action and is useful as atherapeutic agent for cardiovascular diseases such as hypertension,cardiac disease, stroke and the like, or an agent for improving cerebralfunction.

However, there is no report that the above-mentioned compounds have anangiotensin II receptor antagonistic action and a peroxisomeproliferator-activated receptor (PPAR) agonistic action.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a novel compoundsuperior as a pharmaceutical agent for the prophylaxis or treatment ofcardiovascular diseases such as hypertension and the like; metabolicdiseases such as diabetes and the like; central nervous system diseasessuch as dementia and the like; and the like.

The present inventors have conducted intensive studies in an attempt tofind a new compound having a superior pharmacological action andsuperior physicochemical properties so as to provide a pharmaceuticalagent more useful as a prophylactic or therapeutic drug forcardiovascular diseases, metabolic diseases, central nervous systemdiseases, and the like. As a result, they have found that a compoundrepresented by the following formula (I) or a salt thereof (to bereferred to as “compound (I)” in the present specification) has anangiotensin II receptor antagonistic action and a peroxisomeproliferator-activated receptor (PPAR) agonistic action (including apartial agonistic action) and is useful as an agent for the prophylaxisor treatment for cardiovascular diseases such as hypertension, cardiacdisease (cardiac hypertrophy, cardiac failure, myocardial infarction andthe like), arteriosclerosis, kidney disease (diabetic nephropathy,chronic glomerulonephritis and the like), stroke and the like; metabolicdiseases such as dyslipidemia, obesity, diabetes and the like; and/orcentral nervous system diseases such as depression, dementia,Alzheimer's disease and the like, which resulted in the completion ofthe present invention.

Accordingly, the present invention relates to

-   [1] A compound represented by the following formula (I):

wherein

R1 is

(1) an oxo group;(2) a thioxo group;(3) a group represented by the formula: ═N—Rwherein

R is

-   -   (i) an optionally substituted C1-C6 alkyl group;    -   (ii) an optionally substituted C3-C6 cycloalkyl group;    -   (iii) a group represented by the formula: —O—Ra    -   wherein Ra is hydrogen, an optionally substituted C1-C6 alkyl        group or an optionally substituted C3-C6 cycloalkyl group; or    -   (iv) a group represented by the formula: —N(Rb)—Rc    -   wherein Rb and Rc are each independently hydrogen, an optionally        substituted C1-C6 alkyl group or an optionally substituted C3-C6        cycloalkyl group, or Rb and Rc are bonded to each other to form,        together with the nitrogen atom bonded thereto, an optionally        substituted nitrogen-containing heterocyclic group;        (4) a group represented by the formula: ═N—CO—R′        wherein R′ is an optionally substituted C1-C6 alkyl group or an        optionally substituted cyclic group;        (5) a group represented by the formula: ═N—CO—OR′        wherein R′ is as defined above; or        (6) a group represented by the formula: ═N—SO₂—R′        wherein R′ is as defined above; and        a group represented by the formula:

whereinR2 is a group represented by the formula:

wherein R6 is a group represented by the formula:

wherein Z is O or S(O)n (n is an integer of 0 to 2), andY is an optionally substituted C1-C4 alkylene group or a grouprepresented by the formula: —O—W—, —W—O—, —N(Rd)-W— or —W—N(Rd)—wherein W is a bond or an optionally substituted C1-C4 alkylene group,and Rd is an optionally substituted C1-C6 alkyl group or an optionallysubstituted C3-C6 cycloalkyl group (the biphenyl group is optionallyfurther substituted);R3 and R4 are each independently(1) hydrogen,(2) an optionally substituted C1-C6 alkyl group,(3) an optionally substituted C3-C6 cycloalkyl group,(4) an optionally substituted C1-C6 alkoxy group,(5) an optionally substituted C3-C6 cycloalkyloxy group,(6) an optionally substituted C1-C6 alkylamino group,(7) an optionally substituted di(C1-C6)alkylamino group or(8) an optionally substituted C1-C6 alkylthio group; and

R5 is

(1) hydrogen,(2) an optionally substituted C1-C6 alkyl group,(3) an optionally substituted C2-C6 alkenyl group,(4) an optionally substituted cyclic group,(5) a group represented by the formula: —CO—R8wherein R8 is an optionally substituted C1-C6 alkyl group or anoptionally substituted cyclic group, or(6) a group represented by the formula: —O—R8′wherein R8′ is an optionally substituted C1-C6 alkyl group or anoptionally substituted cyclic group,or a salt thereof;

-   [2] The compound of aforementioned [1], wherein R1 is an oxo group;-   [3] The compound of aforementioned [1], wherein R2 is a group    represented by the formula:

wherein R6 is a group represented by the formula:

wherein Z is O or S(O)n (n is an integer of 0 to 2), andY is a C1-C4 alkylene group, (the biphenyl group is optionally furthersubstituted);

-   [4] The compound of aforementioned [3], wherein R2 is a group    represented by the formula:

wherein R13 is(1) hydrogen,(2) halogen,(3) a C1-C6 alkoxy group, or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S;

-   [5] The compound of aforementioned [1], wherein a group represented    by the formula:

wherein R2, R3, R4 and R5 are as defined in aforementioned [1];

-   [6] The compound of aforementioned [5], wherein R3 is    (1) a C1-C6 alkyl group optionally substituted by 1 to 3    substituents selected from the group consisting of a C1-C6 alkoxy    group, halogen, a hydroxy group and a C3-C6 cycloalkyl group;    (2) a C3-C6 cycloalkyl group;    (3) a C1-C6 alkoxy group; or    (4) a C1-C6 alkylthio group;-   [7] The compound of aforementioned [5], wherein R4 is    (1) hydrogen;    (2) a C1-C6 alkyl group optionally substituted by 1 to 3    substituents selected from the group consisting of a C1-C6 alkoxy    group, a hydroxy group, halogen, a cyclic hydrocarbon group and a    heterocyclic group;    (3) a C3-C6 cycloalkyl group;    (4) a C1-C6 alkoxy group; or    (5) a di(C1-C6)alkylamino group;-   [8] The compound of aforementioned [5], wherein R5 is an optionally    substituted C1-C6 alkyl group or an optionally substituted cyclic    group;-   [9] The compound of aforementioned [8], wherein R5 is an optionally    substituted C6-C14 aryl group;-   [10] The compound of aforementioned [9], wherein R5 is a C6-C14 aryl    group optionally substituted by 1 to 3 substituents selected from    the group consisting of    (i) halogen;    (ii) a hydroxy group;    (iii) a C1-C6 alkyl group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen, a    hydroxy group, a C1-C6 alkoxy group and a C1-C6 alkyl-carbonyl    group;    (iv) a C2-C6 alkenyl group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen and a    hydroxy group;    (v) a C1-C6 alkoxy group optionally substituted by 1 to 3    substituents selected from the group consisting of a C2-C6 alkynyl    group, a C1-C6 alkoxy group, halogen, a cyano group, a hydroxy    group, a C3-C6 cycloalkyl group, a C1-C6 alkoxy-carbonyl group and a    carbamoyl group;    (vi) a C2-C6 alkenyloxy group;    (vii) a C2-C6 alkynyloxy group;    (viii) a C1-C6 alkyl-carbonylamino group;    (ix) a C1-C6 alkylthio group;    (x) a C1-C6 alkylsulfinyl group;    (xi) a C1-C6 alkylsulfonyl group;    (xii) a C1-C6 alkyl-carbonyl group;    (xiii) a C1-C6 alkyl-carbamoyl group; and    (xiv) a di(C1-C6)alkyl-carbamoyl group;-   [11]    3-(4-Isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [12]    6-Butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one    or a salt thereof;-   [13]    6-Butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    or a salt thereof;-   [14]    6-Butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    or a salt thereof;-   [15]    6-Butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    or a salt thereof;-   [16]    3-[4-(1-Ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [17]    3-(4-tert-Butoxyphenyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [18]    2-Ethyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [19]    2-Ethyl-3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [20] A crystalline compound of    3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [21] A crystalline compound of hydrate of    3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [22] A crystalline compound of    3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,    which has an X-ray powder diffraction analysis pattern with peaks at    diffraction angle: 2θ(°) of 4.64, 5.46, 8.40, 11.10, 12.60, 13.10,    14.14, 14.36, 14.60, 15.58, 15.86, 16.24, 16.86, 17.52, 19.26,    19.72, 20.00, 20.40, 20.80, 21.12, 21.70;-   [23] A crystalline compound of hydrate of    3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt, which has an X-ray powder diffraction analysis    pattern with peaks at diffraction angle: 2θ(°) of 4.46, 6.32, 12.66,    12.84, 13.46, 13.74, 16.82, 17.08, 17.82, 17.98, 18.38, 19.70,    20.34, 21.80, 22.18, 22.80, 24.08, 25.40, 26.70;-   [24] The compound of aforementioned [9], wherein R5 is a C6-C14 aryl    group optionally substituted by 1 to 3 substituents selected from    the group consisting of    (i) a C3-C6 cycloalkyl group;    (ii) a C3-C10 cycloalkyloxy group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen, an oxo    group, a hydroxy group, a C1-C6 alkyl group, a C1-C6 alkoxy group    optionally substituted by 1 to 3 halogens, a hydroxy-C1-C6 alkyl    group and a C1-C6 alkoxy-C1-C6 alkyl group;    (iii) a C6-C14 aryloxy group;    (iv) a heterocyclyl-oxy group optionally substituted by 1 to 3 C1-C6    alkyl groups;    (v) a heterocyclyl-C1-C6 alkyloxy group; and    (vi) a heterocyclic group;-   [25]    3-[4-(Cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [26]    3-[4-(Cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [27]    3-[4-(Cyclopentyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [28]    2-Ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]pyrimidin-4(3H)-one    or a salt thereof;-   [29]    2-Ethyl-3-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [30]    2-Ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [31]    2-Ethyl-3-{4-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [32]    2-Ethyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [33]    3-(4-{[(2R,4S,6S)-2,6-Dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [34]    2-Ethyl-3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [35] A crystalline compound of    2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [36] A crystalline compound of hydrate of    2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [37] A crystalline compound of    2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,    which has an X-ray powder diffraction analysis pattern with peaks at    diffraction angle: 2θ(°) of 4.60, 8.38, 9.28, 9.66, 10.46, 12.26,    12.86, 13.98, 16.92, 17.32, 18.70, 18.94, 19.62, 20.18, 20.98;-   [38] A crystalline compound of    2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,    which has an X-ray powder diffraction analysis pattern with peaks at    diffraction angle: 2θ(°) of 8.50, 11.86, 12.26, 13.98, 17.14, 18.46,    19.04, 19.28, 19.62, 20.16, 20.48, 22.58, 24.60;-   [39] A crystalline compound of    2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,    which has an X-ray powder diffraction analysis pattern with peaks at    diffraction angle: 2θ(°) of 7.36, 7.66, 11.58, 12.84, 13.28, 13.64,    14.50, 15.28, 15.50, 18.38, 18.66, 19.28, 20.20, 20.70, 21.72,    22.14, 22.82;-   [40] A crystalline compound of    2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,    which has an X-ray powder diffraction analysis pattern with peaks at    diffraction angle: 2θ(°) of 8.34, 9.16, 10.64, 11.08, 11.42, 12.42,    13.18, 13.88, 14.78, 15.58, 16.28, 17.10, 17.80, 18.56, 18.94,    19.18, 20.14, 20.86, 21.56, 22.04, 22.44, 23.14, 23.66, 24.80,    26.18, 27.96, 29.16;-   [41] A crystalline compound of hydrate of    2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt, which has an X-ray powder diffraction analysis    pattern with peaks at diffraction angle: 2θ(°) of 4.32, 8.70, 9.86,    12.76, 13.10, 15.48, 18.36, 19.68, 20.62, 21.36, 21.76, 22.04,    22.44, 23.10, 24.22, 24.62, 27.94, 28.24;-   [42] A crystalline compound of hydrate of    2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt, which has an X-ray powder diffraction analysis    pattern with peaks at diffraction angle: 2θ(°) of 6.32, 6.84, 8.90,    14.36, 16.64, 17.96, 19.18, 19.94, 21.82, 22.04, 22.90, 23.62,    24.92;-   [43] The compound of aforementioned [8], wherein R5 is an optionally    substituted heterocyclic group;-   [44] The compound of aforementioned [43], wherein R5 is a    heterocyclic group optionally substituted by 1 to 3 substituents    selected from the group consisting of    (i) halogen;    (ii) an oxo group;    (iii) a hydroxy group;    (iv) an amino group;    (v) a C1-C6 alkyl group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen, a    hydroxy group and a C1-C6 alkoxy group;    (vi) a C1-C6 alkoxy group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen, a    hydroxy group and a C3-C6 cycloalkyl group;    (vii) a heterocyclyl-oxy group;    (viii) a C1-C6 alkyl-carbonylamino group; and    (ix) a C1-C6 alkoxy-carbonyl group;-   [45]    6-Butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    or a salt thereof;-   [46]    6-Butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    or a salt thereof;-   [47]    6-Butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    or a salt thereof;-   [48]    3-(2,2-Dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [49]    3-(4-Hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [50]    6-Butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    or a salt thereof;-   [51]    2-Methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [52]    3-(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [53]    3-(7-Fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [54] A crystalline compound of    3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [55] A crystalline compound of hydrate of    3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    or a salt thereof;-   [56] A crystalline compound of    3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,    which has an X-ray powder diffraction analysis pattern with peaks at    diffraction angle: 2θ(°) of 4.76, 6.10, 7.30, 7.86, 8.16, 9.18,    9.60, 10.66, 11.28, 11.94, 12.58, 13.34, 14.62, 15.10, 15.46, 16.34,    16.90, 17.76, 18.64, 19.34, 20.86, 21.58, 22.42, 24.36, 24.86;-   [57] A crystalline compound of    3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,    which has an X-ray powder diffraction analysis pattern with peaks at    diffraction angle: 2θ(°) of 4.38, 7.42, 8.90, 9.68, 10.92, 11.24,    11.90, 12.56, 12.88, 13.34, 14.06, 14.92, 16.64, 17.30, 17.80,    18.70, 19.08, 19.40, 20.36, 20.90, 21.20, 21.50, 21.98, 22.40,    22.72, 22.98, 23.68;-   [58] A crystalline compound of hydrate of    3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt, which has an X-ray powder diffraction analysis    pattern with peaks at diffraction angle: 2θ(°) of 5.02, 5.36, 9.46,    10.66, 11.80, 13.42, 17.06, 17.78, 19.00, 19.18, 20.18, 20.88,    21.38, 23.26, 23.78, 25.06, 25.74, 26.06, 26.90, 27.34;-   [59] The compound of aforementioned [8], wherein R5 is an optionally    substituted C1-C6 alkyl group;-   [60] The compound of aforementioned [59], wherein R5 is a C1-C6    alkyl group optionally substituted by 1 to 3 substituents selected    from the group consisting of    (i) a hydroxy group;    (ii) a carboxy group;    (iii) a C1-C6 alkoxy-carbonyl group;    (iv) a C1-C6 alkyl-carbonyl group;    (v) a C3-C10 cycloalkyl-carbonyl group;    (vi) a C6-C14 aryl-carbonyl group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen and a    C1-C6 alkoxy group;    (vii) a heterocyclyl-carbonyl group;    (viii) a C1-C6 alkyl-carbamoyl group;    (ix) a C3-C6 cycloalkyl group;    (x) an adamantyl group;    (xi) a C6-C14 aryl group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen; a C1-C6    alkyl group optionally substituted by 1 to 3 substituents selected    from the group consisting of halogen, a hydroxy group and a C1-C6    alkoxy group; a C1-C6 alkoxy group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen and a    hydroxy group; a C1-C6 alkylsulfonyl group; a carboxy group; a C1-C6    alkoxy-carbonyl group; a C1-C6 alkyl-carbonyl group; and a    heterocyclyl-carbonyl group;    (xii) a heterocyclic group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen; a    hydroxy group; a C1-C6 alkyl group optionally substituted by 1 to 3    substituents selected from the group consisting of halogen, a    hydroxy group and a C1-C6 alkoxy group; a C6-C14 aryl group; a    C7-C16 aralkyl group; a heterocyclic group; and a C1-C6 alkoxy group    optionally substituted by 1 to 3 substituents selected from the    group consisting of halogen and a hydroxy group; and    (xiii) a C1-C6 alkoxyimino group;-   [61]    6-Butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one;-   6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one;-   3-benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one;-   6-butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one;-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one;-   6-butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one;-   3-(1,3-benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one;-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one;-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-one;    or-   6-butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one;    or a salt thereof;-   [62] The compound of aforementioned [1], wherein the group    represented by the formula:

is a group represented by the formula:

wherein R2, R3, R4 and R5 are as defined in aforementioned

-   [1];-   [63] The compound of aforementioned [62], wherein R3 is    (1) a C1-C6 alkyl group optionally substituted by 1 to 3    substituents selected from the group consisting of a C1-C6 alkoxy    group, halogen, a hydroxy group and a C3-C6 cycloalkyl group;    (2) a C3-C6 cycloalkyl group;    (3) a C1-C6 alkoxy group; or    (4) a C1-C6 alkylthio group;-   [64] The compound of aforementioned [62], wherein R4 is    (1) hydrogen;    (2) a C1-C6 alkyl group optionally substituted by 1 to 3    substituents selected from the group consisting of a C1-C6 alkoxy    group, a hydroxy group, halogen, a cyclic hydrocarbon group and a    heterocyclic group;    (3) a C3-C6 cycloalkyl group;    (4) a C1-C6 alkoxy group; or    (5) a di(C1-C6)alkylamino group;-   [65] The compound of aforementioned [62], wherein R5 is an    optionally substituted C1-C6 alkyl group or an optionally    substituted cyclic group;-   [66]    5-Benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one;-   6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one;-   5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one;-   5-benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one;-   2-butyl-5-[hydroxy(phenyl)methyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one;-   5-benzoyl-2-butyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one;-   6-ethyl-5-(morpholin-4-ylmethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one;-   6-ethyl-5-(1-hydroxy-2-methylpropyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one;-   6-ethyl-5-(6-isopropoxypyridin-3-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one;    or-   6-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one;    or a salt thereof;-   [67] The compound of aforementioned [1], wherein the group    represented by the formula:

is a group represented by the formula:

wherein R2, R3 and R5 are as defined in aforementioned [1];

-   [68] The compound of aforementioned [67], wherein R3 is a C1-C6    alkyl group;-   [69] The compound of aforementioned [67], wherein R5 is an    optionally substituted C1-C6 alkyl group or an optionally    substituted cyclic group;-   [70]    3-(4′-{[3-Butyl-1-(2,2-dimethylpropyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-(4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-(4′-{[3-butyl-5-oxo-1-(2-phenylethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-{4′-[(3-butyl-1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-{4′-[(3-butyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-yl}-1,2,4-oxadiazol-5(4H)-one;-   3-(4′-{[3-butyl-5-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one;-   3-[4′-({3-butyl-1-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-yl]-1,2,4-oxadiazol-5(4H)-one;-   3-[4′-({3-butyl-1-[2-(4-methoxyphenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-yl]-1,2,4-oxadiazol-5(4H)-one;    or-   3-(4′-{[3-butyl-1-(3,3-dimethyl-2-oxobutyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one;    or a salt thereof;-   [71] A prodrug of the compound of aforementioned [1];-   [72] A pharmaceutical agent comprising the compound of    aforementioned [1] or a prodrug thereof as an active ingredient;-   [73] The pharmaceutical agent of aforementioned [72], which has an    angiotensin II receptor inhibitory activity and/or a peroxisome    proliferator-activated receptor agonistic activity;-   [74] The pharmaceutical agent of aforementioned [72], which is an    agent for the prophylaxis or treatment of cardiovascular diseases,    metabolic diseases and/or central nervous system diseases;-   [75] The pharmaceutical agent of aforementioned [72], which is an    agent for the prophylaxis or treatment of hypertension, cardiac    disease, arteriosclerosis, kidney disease, stroke, dyslipidemia,    obesity, diabetes, nonalcoholic steatohepatitis, dementia and/or    Alzheimer's disease;-   [76] A method for inhibiting an angiotensin II receptor and/or    activating a peroxisome proliferator-activated receptor in a mammal,    which comprises administering the compound of aforementioned [1] or    a prodrug thereof to said mammal;-   [77] A method for preventing or treating cardiovascular diseases,    metabolic diseases and/or central nervous system diseases in a    mammal, which comprises administering the compound of aforementioned    [1] or a prodrug thereof to said mammal;-   [78] A method for preventing or treating hypertension, cardiac    disease, arteriosclerosis, kidney disease, stroke, dyslipidemia,    obesity, diabetes, nonalcoholic steatohepatitis, dementia and/or    Alzheimer's disease in a mammal, which comprises administering the    compound of aforementioned [1] or a prodrug thereof to said mammal;    and the like.

DETAILED DESCRIPTION OF THE INVENTION

The definition of each symbol used in the present specification isdescribed in detail in the following.

In the present specification, the “halogen” is fluorine, chlorine,bromine or iodine.

In the present specification, the “C1-C6 alkyl group” is, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl,—CH₂CH₂C(CH₃)₃ or the like.

In the present specification, the “C2-C6 alkenyl group” is, for example,vinyl, allyl, propenyl, isopropenyl, but-3-en-1-yl, pent-4-en-1-yl,hex-5-en-1-yl, 2-methylprop-1-en-1-yl or the like.

In the present specification, the “C2-C6 alkynyl group” is, for example,ethynyl, prop-2-yn-1-yl, but-3-yn-1-yl, pent-4-yn-1-yl, hex-5-yn-1-yl orthe like.

In the present specification, the “C3-C6 cycloalkyl group” iscyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

In the present specification, the “C6-C14 aryl group” is, for example,phenyl, naphthyl (e.g., 1-naphthyl, 2-naphthyl), anthryl, phenanthryl orthe like, preferably phenyl or naphthyl, more preferably phenyl.

In the present specification, the “C7-C16 aralkyl group” is, forexample, benzyl, 1-phenylethyl, 2-phenylethyl, naphthylmethyl(1-naphthylmethyl, 2-naphthylmethyl), 3-phenylpropyl, 4-phenylbutyl,5-phenylpentyl or the like.

In the present specification, the “C1-C6 alkoxy group” is, for example,methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy,tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy,hexyloxy, —OCH(CH₂CH₃)₂ or the like.

In the present specification, the “optionally halogenated C1-C6 alkylgroup” is the above-mentioned “C1-C6 alkyl group” optionally substitutedby 1 to 5 of the above-mentioned “halogen”. For example, methyl, ethyl,propyl, isopropyl, butyl, tert-butyl, isobutyl, trifluoromethyl and thelike can be mentioned.

In the present specification, the “optionally halogenated C1-C6 alkoxygroup” is the above-mentioned “C1-C6 alkoxy group” optionallysubstituted by 1 to 5 of the above-mentioned “halogen”. For example,methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy,trifluoromethoxy, 2-fluoroethoxy and the like can be mentioned.

In the present specification, the “heterocyclic group” is, unlessotherwise specified, for example, a 4- to 14-membered (preferably 5- to10-membered) (monocyclic, bicyclic or tricyclic) heterocyclic group,preferably (i) a 5- to 14-membered (preferably 5- to 10-membered)aromatic heterocyclic group, (ii) a 4- to 10-membered (preferably 5- to10-membered) non-aromatic heterocyclic group, each containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom or the like.

The “aromatic heterocyclic group” is, for example, a monocyclic aromaticheterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl or the like; or an aromatic fusedheterocyclic group such as benzofuryl, isobenzofuryl, benzo[b]thienyl,indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,benzo[d]isoxazolyl, benzothiazolyl, benzo[d]isothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-a]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl or the like.

The “non-aromatic heterocyclic group” is, for example, a monocyclicnon-aromatic heterocyclic group such as azetidinyl, oxetanyl, thietanyl,pyrrolidinyl, tetrahydrofuryl, thiolanyl, imidazolidinyl, pyrazolidinyl,oxazolidinyl, thiazolidinyl, piperidyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, piperazinyl or the like; or a non-aromatic fusedheterocyclic group such as isochromanyl, dihydrobenzopyranyl,isochromenyl, chromenyl (2H-chromenyl, 4H-chromenyl),1,2,3,4-tetrahydroisoquinolyl, 1,2,3,4-tetrahydroquinolyl,2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl or the like.

In the present specification, the “C2-C6 alkenyloxy group” is, forexample, vinyloxy, allyloxy, propenyloxy, isopropenyloxy,but-3-en-1-yloxy, pent-4-en-1-yloxy, hex-5-en-1-yloxy or the like.

In the present specification, the “C2-C6 alkynyloxy group” is, forexample, ethynyloxy, prop-2-yn-1-yloxy, but-3-yn-1-yloxy,pent-4-yn-1-yloxy, hex-5-yn-1-yloxy, 1-methylbut-3-yn-1-yloxy or thelike.

In the present specification, the “C3-C6 cycloalkyloxy group” iscyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy.

In the present specification, the “C3-C10 cycloalkyloxy group” iscyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy,cycloheptyloxy, cyclooctyloxy or the like.

In the present specification, the “C6-C14 aryloxy group” is, forexample, phenoxy, 1-naphthyloxy, 2-naphthyloxy or the like.

In the present specification, the “C7-C16 aralkyloxy group” is, forexample, benzyloxy, phenethyloxy or the like.

In the present specification, the “heterocyclyl-oxy group” is, forexample, a heterocyclyl-oxy group wherein the heterocyclyl moiety is a5- or 6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom. Preferable examples of the “heterocyclyl-oxy group”include tetrahydrofuranyloxy (e.g., tetrahydrofuran-3-yloxy),tetrahydropyranyloxy (e.g., tetrahydropyran-4-yloxy), piperidinyloxy(e.g., piperidin-4-yloxy) and the like.

In the present specification, the “heterocyclyl-C1-C6 alkyloxy group”is, for example, a heterocyclyl-(C1-C6)alkyloxy group wherein theheterocyclyl moiety is a 5- or 6-membered, aromatic or non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms of 1 or 2 kinds selected from the group consistingof nitrogen atom, sulfur atom and oxygen atom. Preferable examples ofthe “heterocyclyl-C1-C6 alkyloxy group” include tetrahydrofuranylmethoxy(e.g., tetrahydrofuran-3-ylmethoxy), tetrahydropyranylmethoxy (e.g.,tetrahydropyran-4-ylmethoxy), piperidinylmethoxy (e.g.,piperidin-4-ylmethoxy) and the like.

In the present specification, the “C1-C6 alkylamino group” is, forexample, an amino group monosubstituted by the above-mentioned “C1-C6alkyl group”. For example, methylamino, ethylamino, propylamino,isopropylamino, butylamino, isobutylamino, sec-butylamino,tert-butylamino, pentylamino, isopentylamino, neopentylamino,tert-pentylamino, hexylamino and the like can be mentioned.

In the present specification, the “di(C1-C6)alkylamino group” is, forexample, an amino group disubstituted by the above-mentioned “C1-C6alkyl group”. For example, dimethylamino, diethylamino,N-ethyl-N-methylamino and the like can be mentioned.

In the present specification, the “C6-C14 arylamino group” is, forexample, an amino group monosubstituted by the above-mentioned “C6-C14aryl group”. For example, phenylamino, 1-naphthylamino, 2-naphthylaminoand the like can be mentioned.

In the present specification, the “di(C6-C14)arylamino group” is, forexample, an amino group disubstituted by the above-mentioned “C6-C14aryl group”. For example, diphenylamino, dinaphthylamino and the likecan be mentioned.

In the present specification, the “C7-C16 aralkylamino group” is, forexample, an amino group monosubstituted by the above-mentioned “C7-C16aralkyl group”. For example, benzylamino, phenethylamino and the likecan be mentioned.

In the present specification, the “di(C7-C16)aralkylamino group” is, forexample, an amino group disubstituted by the above-mentioned “C7-C16aralkyl group”. For example, dibenzylamino, diphenethylamino and thelike can be mentioned.

In the present specification, the “N—(C1-C6)alkyl-N—(C6-C14)arylaminogroup” is, for example, an amino group substituted by theabove-mentioned “C1-C6 alkyl group” and the above-mentioned “C6-C14 arylgroup”. For example, N-methyl-N-phenylamino, N-ethyl-N-phenylamino andthe like can be mentioned.

In the present specification, the “N—(C1-C6)alkyl-N—(C7-C16)aralkylaminogroup” is, for example, an amino group substituted by theabove-mentioned “C1-C6 alkyl group” and the above-mentioned “C7-C16aralkyl group”. For example, N-methyl-N-benzylamino,N-ethyl-N-benzylamino and the like can be mentioned.

In the present specification, the “C1-C6 alkyl-carbonylamino group” is,for example, acetylamino, propanoylamino, butanoylamino,2-methylpropanoylamino, pentanoylamino, 3-methylbutanoylamino,2,2-dimethylpropanoylamino or the like.

In the present specification, the “C1-C6 alkylthio group” is, forexample, methylthio, ethylthio, propylthio, isopropylthio, butylthio,sec-butylthio, tert-butylthio or the like.

In the present specification, the “C1-C6 alkylsulfinyl group” is, forexample, methylsulfinyl, ethylsulfinyl, propylsulfinyl,isopropylsulfinyl, butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinylor the like.

In the present specification, the “C1-C6 alkylsulfonyl group” is, forexample, methylsulfonyl, ethylsulfonyl, propylsulfonyl,isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonylor the like.

In the present specification, the “optionally esterified carboxy group”is, for example, carboxy group, C1-C6 alkoxy-carbonyl group (e.g.,methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyland the like), C6-C14 aryloxy-carbonyl group (e.g., phenoxycarbonyl andthe like), C7-C16 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,phenethyloxycarbonyl and the like) or the like.

In the present specification, the “C1-C6 alkyl-carbonyl group” is, forexample, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl,3-methylbutanoyl, 2,2-dimethylpropanoyl or the like.

In the present specification, the “C3-C10 cycloalkyl-carbonyl group” is,for example, cyclopentylcarbonyl, cyclohexylcarbonyl, adamantylcarbonylor the like.

In the present specification, the “C6-C14 aryl-carbonyl group” is, forexample, benzoyl, 1-naphthoyl, 2-naphthoyl or the like.

In the present specification, the “C7-C16 aralkyl-carbonyl group” is,for example, phenylacetyl, 3-phenylpropanoyl or the like.

In the present specification, the “C1-C6 alkoxy-carbonyl group” is, forexample, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl,tert-butoxycarbonyl or the like.

In the present specification, the “C6-C14 aryloxy-carbonyl group” is,for example, phenoxycarbonyl, 1-naphthyloxycarbonyl,2-naphthyloxycarbonyl or the like.

In the present specification, the “C7-C16 aralkyloxy-carbonyl group” is,for example, benzyloxycarbonyl, phenethyloxycarbonyl or the like.

In the present specification, the “heterocyclyl-carbonyl group” is, forexample, a heterocyclyl-carbonyl group wherein the heterocyclyl moietyis a 5- or 6-membered, aromatic or non-aromatic heterocycle containing,as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms of1 or 2 kinds selected from the group consisting of nitrogen atom, sulfuratom and oxygen atom. Preferable examples of the “heterocyclyl-carbonylgroup” include 1-pyrrolidinylcarbonyl, piperidinocarbonyl,1-piperazinylcarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl andthe like.

In the present specification, the “C1-C6 alkyl-carbamoyl group” is, forexample, a carbamoyl group monosubstituted by the above-mentioned “C1-C6alkyl group”. For example, methylcarbamoyl, ethylcarbamoyl and the likecan be mentioned.

In the present specification, the “di(C1-C6)alkyl-carbamoyl group” is,for example, a carbamoyl group disubstituted by the above-mentioned“C1-C6 alkyl group”. For example, dimethylcarbamoyl, diethylcarbamoyl,N-ethyl-N-methylcarbamoyl and the like can be mentioned.

In the present specification, the “C6-C14 aryl-carbamoyl group” is, forexample, a carbamoyl group monosubstituted by the above-mentioned“C6-C14 aryl group”. For example, phenylcarbamoyl, 1-naphthylcarbamoyl,2-naphthylcarbamoyl and the like can be mentioned.

In the present specification, the “di(C6-C14)aryl-carbamoyl group” is,for example, a carbamoyl group disubstituted by the above-mentioned“C6-C14 aryl group”. For example, diphenylcarbamoyl, dinaphthylcarbamoyland the like can be mentioned.

In the present specification, the “C1-C6 alkylsulfamoyl group” is, forexample, a sulfamoyl group monosubstituted by the above-mentioned “C1-C6alkyl group”. For example, methylsulfamoyl, ethylsulfamoyl and the likecan be mentioned.

In the present specification, the “di(C1-C6)alkylsulfamoyl group” is,for example, a sulfamoyl group disubstituted by the above-mentioned“C1-C6 alkyl group”. For example, dimethylsulfamoyl, diethylsulfamoyl,N-ethyl-N-methylsulfamoyl and the like can be mentioned.

In the present specification, the “C6-C14 arylsulfamoyl group” is, forexample, a sulfamoyl group monosubstituted by the above-mentioned“C6-C14 aryl group”. For example, phenylsulfamoyl, 1-naphthylsulfamoyl,2-naphthylsulfamoyl and the like can be mentioned.

In the present specification, the “di(C6-C14)arylsulfamoyl group” is,for example, a sulfamoyl group disubstituted by the above-mentioned“C6-C14 aryl group”. For example, diphenylsulfamoyl, dinaphthylsulfamoyland the like can be mentioned.

In the present specification, the “C1-C6 alkoxyimino group” is, forexample, methoxyimino, ethoxyimino, propoxyimino, isopropoxyimino,butoxy imino, isobutoxyimino, sec-butoxy imino, tert-butoxy imino,pentyloxyimino, hexyloxyimino or the like.

In the present specification, the “hydroxy-C1-C6 alkyl group” is, forexample, hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl, 3-hydroxypropyl,1-hydroxy-1-methylethyl or the like.

In the present specification, the “C1-C6 alkoxy-C1-C6 alkyl group” is,for example, methoxymethyl, 2-methoxyethyl, 1-methoxyethyl,ethoxymethyl, 2-ethoxyethyl or the like.

In the present specification, the “optionally substituted C1-C6 alkylgroup”, “optionally substituted C2-C6 alkenyl group”, “optionallysubstituted C2-C6 alkynyl group”, “optionally substituted C1-C6 alkoxygroup” or “optionally substituted C1-C6 alkylthio group” is, forexample, “C1-C6 alkyl group”, “C2-C6 alkenyl group”, “C2-C6 alkynylgroup”, “C1-C6 alkoxy group” or “C1-C6 alkylthio group”, each optionallysubstituted by 1 to 5, preferably 1 to 3, substituents selected from thegroup consisting of

(1) halogen,(2) a hydroxy group,(3) an amino group,(4) a nitro group,(5) a cyano group,(6) an optionally halogenated C1-C6 alkoxy group,(7) a C3-C6 cycloalkyloxy group,(8) a C6-C14 aryloxy group,(9) a C7-C16 aralkyloxy group,(10) a C1-C6 alkylamino group,(11) a di(C1-C6)alkylamino group,(12) a C6-C14 arylamino group,(13) a di(C6-C14)arylamino group,(14) a C7-C16 aralkylamino group,(15) a di(C7-C16)aralkylamino group,(16) a N—(C1-C6)alkyl-N—(C6-C14)arylamino group,(17) an N—(C1-C6)alkyl-N—(C7-C16)aralkylamino group,(18) a C1-C6 alkyl-carbonylamino group,(19) a C1-C6 alkylthio group,(20) a C1-C6 alkylsulfinyl group,(21) a C1-C6 alkylsulfonyl group,(22) an optionally esterified carboxy group,(23) a C1-C6 alkyl-carbonyl group,(24) a C3-C10 cycloalkyl-carbonyl group,(25) an optionally substituted C6-C14 aryl-carbonyl group,(26) a C7-C16 aralkyl-carbonyl group,(27) a heterocyclyl-carbonyl group,(28) a carbamoyl group,(29) a thiocarbamoyl group,(30) a C1-C6 alkyl-carbamoyl group,(31) a di(C1-C6)alkyl-carbamoyl group,(32) a C6-C14 aryl-carbamoyl group,(33) a di(C6-C14)aryl-carbamoyl group,(34) a sulfamoyl group,(35) a C1-C6 alkylsulfamoyl group,(36) a di(C1-C6)alkylsulfamoyl group,(37) a C6-C14 arylsulfamoyl group,(38) a di(C6-C14)arylsulfamoyl group,(39) an optionally substituted cyclic group,(40) a C1-C6 alkoxyimino group,and the like. Here, the “optionally substituted cyclic group” includes,for example, those similar to the below-mentioned “optionallysubstituted cyclic group” for R5.

In the present specification, the “C6-C14 aryl-carbonyl group” of the“optionally substituted C6-C14 aryl-carbonyl group” optionally has 1 to5, preferably 1 to 3, substituents at substitutable position(s).Examples of such substituent include halogen, a hydroxy group, anoptionally halogenated C1-C6 alkyl group, an optionally halogenatedC1-C6 alkoxy group, an amino group, a C1-C6 alkylamino group, adi(C1-C6)alkylamino group, a C1-C6 alkylthio group, a C1-C6alkylsulfonyl group, a carboxy group, a C1-C6 alkoxy-carbonyl group, aC1-C6 alkyl-carbonyl group and the like.

In the present specification, the “optionally substituted C1-C6alkylamino group” is, for example, an amino group monosubstituted by theabove-mentioned “optionally substituted C1-C6 alkyl group”.

In the present specification, the “optionally substituteddi(C1-C6)alkylamino group” is, for example, an amino group disubstitutedby the above-mentioned “optionally substituted C1-C6 alkyl group”.

In the aforementioned formulas, R5 is hydrogen, an optionallysubstituted C1-C6 alkyl group, an optionally substituted C2-C6 alkenylgroup, an optionally substituted cyclic group, a group represented bythe formula: —CO—R8 wherein R8 is an optionally substituted C1-C6 alkylgroup or an optionally substituted cyclic group, or a group representedby the formula: —O—R8′ wherein R8′ is an optionally substituted C1-C6alkyl group or an optionally substituted cyclic group.

Preferably, R5 is an optionally substituted C1-C6 alkyl group or anoptionally substituted cyclic group, more preferably an optionallysubstituted cyclic group.

The “cyclic group” of the “optionally substituted cyclic group” for R5is, for example, a cyclic hydrocarbon group or a heterocyclic group.

The “cyclic hydrocarbon group” is, for example, an alicyclic hydrocarbongroup constituted by 3 to 14 carbon atoms, an aromatic hydrocarbon groupconstituted by 6 to 14 carbon atoms, or the like.

The “alicyclic hydrocarbon group” is, for example, a C3-C6 cycloalkylgroup (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and thelike), a C3-C6 cycloalkenyl group (e.g., cyclopentenyl, cyclohexenyl andthe like), a C5-C14 cycloalkadienyl group (e.g., 2,4-cyclopentadienyl,1,3-cyclohexadienyl and the like), an indanyl group, an adamantyl groupor the like.

The “aromatic hydrocarbon group” is, for example, a C6-C14 aryl group(e.g., phenyl, naphthyl, anthryl, phenanthryl and the like) or the like.

The “heterocyclic group” is, for example, a 4- to 14-membered(preferably 5- to 10-membered) (monocyclic, bicyclic or tricyclic)heterocyclic group, preferably (i) a 5- to 14-membered (preferably 5- to10-membered) aromatic heterocyclic group or (ii) a 4- to 10-membered(preferably 5- to 10-membered) non-aromatic heterocyclic group, eachcontaining, as a ring-constituting atom besides carbon atom, 1 to 4hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or the like.

The “aromatic heterocyclic group” is, for example, a monocyclic aromaticheterocyclic group such as furyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, furazanyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, triazinyl or the like; or an aromatic fusedheterocyclic group such as benzofuryl, isobenzofuryl, benzo[b]thienyl,indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl,benzo[d]isoxazolyl, benzothiazolyl, benzo[d]isothiazolyl,1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl,quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl,carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl,phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl,phenanthridinyl, phenanthrolinyl, indolizinyl,pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl,imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-a]pyridazinyl,imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl,1,2,4-triazolo[4,3-b]pyridazinyl or the like.

The “non-aromatic heterocyclic group” is, for example, a monocyclicnon-aromatic heterocyclic group such as oxiranyl, azetidinyl, oxetanyl,thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, imidazolidinyl,pyrazolidinyl, oxazolidinyl, thiazolidinyl, piperidyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl or thelike; or a non-aromatic fused heterocyclic group such as isochromanyl,dihydrobenzopyranyl, isochromenyl, chromenyl (2H-chromenyl,4H-chromenyl), 1,2,3,4-tetrahydroisoquinolyl,1,2,3,4-tetrahydroquinolyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolylor the like.

The “cyclic group” of the “optionally substituted cyclic group” for R5is preferably a C3-C6 cycloalkyl group, a C3-C6 cycloalkenyl group, anindanyl group, a C6-C14 aryl group, a heterocyclic group or the like,more preferably a C6-C14 aryl group or a heterocyclic group.

The “cyclic group” of the “optionally substituted cyclic group” for R5optionally has 1 to 5, preferably 1 to 3, substituents at substitutableposition(s). Such substituent includes, for example,

(1) halogen,(2) an oxo group,(3) a hydroxy group,(4) an amino group,(5) a nitro group,(6) a cyano group,(7) a C1-C6 alkyl group,(8) a C2-C6 alkenyl group,(9) a C2-C6 alkynyl group,(10) a C3-C6 cycloalkyl group,(11) a C6-C14 aryl group,(12) a C7-C16 aralkyl group,(13) a heterocyclic group,(14) a C1-C6 alkoxy group,(15) a C2-C6 alkenyloxy group,(16) a C2-C6 alkynyloxy group,(17) an optionally substituted C3-C10 cycloalkyloxy group (preferably, aC3-C10 cycloalkyloxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, an oxo group, a hydroxygroup, a C1-C6 alkyl group, a C1-C6 alkoxy group optionally substitutedby 1 to 3 halogens, a hydroxy-C1-C6 alkyl group and a C1-C6 alkoxy-C1-C6alkyl group),(18) a C6-C14 aryloxy group,(19) a C7-C16 aralkyloxy group,(20) an optionally substituted heterocyclyl-oxy group (preferably, aheterocyclyl-oxy group optionally substituted by 1 to 3 C1-C6 alkylgroups),(21) a heterocyclyl-C1-C6 alkyloxy group,(22) a C1-C6 alkylamino group,(23) a di(C1-C6)alkylamino group,(24) a C6-C14 arylamino group,(25) a di(C6-C14)arylamino group,(26) a C7-C16 aralkylamino group,(27) a di(C7-C16)aralkylamino group,(28) an N—(C1-C6)alkyl-N—(C6-C14)arylamino group,(29) an N—(C1-C6)alkyl-N—(C7-C16)aralkylamino group,(30) a C1-C6 alkyl-carbonylamino group,(31) a C1-C6 alkylthio group,(32) a C1-C6 alkylsulfinyl group,(33) a C1-C6 alkylsulfonyl group,(34) an optionally esterified carboxy group,(35) a C1-C6 alkyl-carbonyl group,(36) a C3-C6 cycloalkyl-carbonyl group,(37) a C6-C14 aryl-carbonyl group,(38) a C7-C16 aralkyl-carbonyl group,(39) a heterocyclyl-carbonyl group,(40) a carbamoyl group,(41) a thiocarbamoyl group,(42) a C1-C6 alkyl-carbamoyl group,(43) a di(C1-C6)alkyl-carbamoyl group,(44) a C6-C14 aryl-carbamoyl group,(45) a di(C6-C14)aryl-carbamoyl group,(46) a sulfamoyl group,(47) a C1-C6 alkylsulfamoyl group,(48) a di(C1-C6)alkylsulfamoyl group,(49) a C6-C14 arylsulfamoyl group,(50) a di(C6-C14)arylsulfamoyl group,and the like. Here, the “C1-C6 alkyl group”, “C2-C6 alkenyl group” and“C2-C6 alkynyl group” are each optionally substituted by 1 to 3substituents selected from the group consisting of a C1-C6 alkoxy group,halogen, a cyano group, a hydroxy group, a C1-C6 alkylamino group, adi(C1-C6)alkylamino group, a C3-C6 cycloalkyl group, a C1-C6alkyl-carbonyl group, a C1-C6 alkoxy-carbonyl group and a carbamoylgroup. In addition, the “C1-C6 alkoxy group” is optionally substitutedby 1 to 3 substituents selected from the group consisting of a C2-C6alkynyl group, a C1-C6 alkoxy group, halogen, a cyano group, a hydroxygroup, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a C3-C6cycloalkyl group, a C1-C6 alkyl-carbonyl group, a C1-C6 alkoxy-carbonylgroup and a carbamoyl group.

The “optionally substituted cyclic group” for R5 is preferably a cyclicgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of

(1) a C1-C6 alkyl group,(2) a C2-C6 alkenyl group,(3) a C3-C6 cycloalkyl group,(4) an oxo group,(5) a hydroxy group,(6) an amino group,(7) a C1-C6 alkoxy group,(8) a C2-C6 alkenyloxy group,(9) a C2-C6 alkynyloxy group,(10) an optionally substituted C3-C10 cycloalkyloxy group (preferably, aC3-C10 cycloalkyloxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, an oxo group, a hydroxygroup, a C1-C6 alkyl group, a C1-C6 alkoxy group optionally substitutedby 1 to 3 halogens, a hydroxy-C1-C6 alkyl group and a C1-C6 alkoxy-C1-C6alkyl group),(11) a C6-C14 aryloxy group,(12) an optionally substituted heterocyclyl-oxy group (preferably, aheterocyclyl-oxy group optionally substituted by 1 to 3 C1-C6 alkylgroups),(13) a heterocyclyl-C1-C6 alkyloxy group,(14) a C1-C6 alkylamino group,(15) a di(C1-C6)alkylamino group,(16) a C1-C6 alkyl-carbonylamino group,(17) a C1-C6 alkylthio group,(18) a C1-C6 alkylsulfinyl group,(19) a C1-C6 alkylsulfonyl group,(20) a C1-C6 alkoxy-carbonyl group,(21) a C1-C6 alkyl-carbonyl group,(22) a C1-C6 alkyl-carbamoyl group,(23) a di(C1-C6)alkyl-carbamoyl group,(24) a heterocyclic group,(25) halogen(wherein the “C1-C6 alkyl group” and “C2-C6 alkenyl group” are eachoptionally substituted by 1 to 3 substituents selected from the groupconsisting of a C1-C6 alkoxy group, halogen, a cyano group, a hydroxygroup, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, a C3-C6cycloalkyl group, a C1-C6 alkyl-carbonyl group, a C1-C6 alkoxy-carbonylgroup and a carbamoyl group, and the “C1-C6 alkoxy group” is optionallysubstituted by 1 to 3 substituents selected from the group consisting ofa C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, a cyano group, ahydroxy group, a C1-C6 alkylamino group, a di(C1-C6)alkylamino group, aC3-C6 cycloalkyl group, a C1-C6 alkyl-carbonyl group, a C1-C6alkoxy-carbonyl group and a carbamoyl group) and the like.

The “optionally substituted cyclic group” for R5 is more preferably

(1) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like),(2) a C3-C6 cycloalkenyl group (e.g., cyclohexenyl and the like),(3) an indanyl group optionally substituted by an oxo group or a hydroxygroup,(4) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like, preferablyphenyl) optionally substituted by 1 to 3 substituents selected from thegroup consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group, a C1-C6alkoxy group and a C1-C6 alkyl-carbonyl group (e.g., methyl, ethyl,isopropyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(vi) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, acyano group, a hydroxy group, a C3-C6 cycloalkyl group, a C1-C6alkoxy-carbonyl group and a carbamoyl group;(vii) a C2-C6 alkenyloxy group (e.g., vinyloxy and the like);(viii) a C2-C6 alkynyloxy group (e.g., 1-methylbut-3-yn-1-yloxy and thelike);(ix) a C3-C10 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, an oxo group, a hydroxy group, a C1-C6 alkyl group, a C1-C6alkoxy group optionally substituted by 1 to 3 halogens, a hydroxy-C1-C6alkyl group and a C1-C6 alkoxy-C1-C6 alkyl group;(x) a C6-C14 aryloxy group (e.g., phenoxy and the like);(xi) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydrofuranyloxy, tetrahydropyranyloxy, piperidinyloxy and the like)optionally substituted by 1 to 3 C1-C6 alkyl groups;(xii) a heterocyclyl-C1-C6 alkyloxy group (preferably, aheterocyclyl-C1-C6 alkyloxy group wherein the heterocyclyl moiety is 5-or 6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., tetrahydropyranylmethoxy and the like);(xiii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(xiv) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(xv) a C1-C6 alkylsulfinyl group (e.g., methylsulfinyl,isopropylsulfinyl and the like)(xvi) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xvii) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xviii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xix) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl and thelike);(xx) a heterocyclic group (preferably, 5- or 6-membered, aromatic ornon-aromatic heterocyclic group containing, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected fromthe group consisting of nitrogen atom, sulfur atom and oxygen atom)(e.g., morpholinyl and the like), and the like,(5) a heterocyclic group (preferably, 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, isoxazolyl, pyrazolyl, pyridyl,dihydrobenzopyranyl, chromenyl, 2,3-dihydrobenzofuranyl,1,3-benzodioxolyl, tetrahydropyranyl, indolyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC1-C6 alkoxy group (e.g., methyl, ethyl, tert-butyl, trifluoromethyl,hydroxymethyl, 1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC3-C6 cycloalkyl group (e.g., methoxy, ethoxy, isopropoxy, neopentyloxy,trifluoromethoxy and the like);(vii) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydropyranyloxy and the like);(viii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(ix) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and the like)and the like,or the like.

The “C1-C6 alkyl group” of the “optionally substituted C1-C6 alkylgroup” or “C2-C6 alkenyl group” of the “optionally substituted C2-C6alkenyl group” for R5 optionally has 1 to 5, preferably 1 to 3,substituents at substitutable position(s). Such substituent includes,for example,

(1) halogen,(2) a hydroxy group,(3) an amino group,(4) a nitro group,(5) a cyano group,(6) an optionally halogenated C1-C6 alkoxy group,(7) a C3-C6 cycloalkyloxy group,(8) a C6-C14 aryloxy group,(9) a C7-C16 aralkyloxy group,(10) a C1-C6 alkylamino group,(11) a di(C1-C6)alkylamino group,(12) a C6-C14 arylamino group,(13) a di(C6-C14)arylamino group,(14) a C7-C16 aralkylamino group,(15) a di(C7-C16)aralkylamino group,(16) an N—(C1-C6)alkyl-N—(C6-C14)arylamino group,(17) an N—(C1-C6)alkyl-N—(C7-C16)aralkylamino group,(18) a C1-C6 alkyl-carbonylamino group,(19) a C1-C6 alkylthio group,(20) a C1-C6 alkylsulfinyl group,(21) a C1-C6 alkylsulfonyl group,(22) an optionally esterified carboxy group,(23) a C1-C6 alkyl-carbonyl group,(24) a C3-C10 cycloalkyl-carbonyl group,(25) an optionally substituted C6-C14 aryl-carbonyl group,(26) a C7-C16 aralkyl-carbonyl group,(27) a heterocyclyl-carbonyl group,(28) a carbamoyl group,(29) a thiocarbamoyl group,(30) a C1-C6 alkyl-carbamoyl group,(31) a di(C1-C6)alkyl-carbamoyl group,(32) a C6-C14 aryl-carbamoyl group,(33) a di(C6-C14)aryl-carbamoyl group,(34) a sulfamoyl group,(35) a C1-C6 alkylsulfamoyl group,(36) a di(C1-C6)alkylsulfamoyl group,(37) a C6-C14 arylsulfamoyl group,(38) a di(C6-C14)arylsulfamoyl group,(39) an optionally substituted cyclic group,(40) a C1-C6 alkoxyimino group,and the like.

The “optionally substituted C6-C14 aryl-carbonyl group” as a substituentof the above-mentioned “optionally substituted C1-C6 alkyl group” or“optionally substituted C2-C6 alkenyl group” for R5 is preferably aC6-C14 aryl-carbonyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a C1-C6 alkoxy group.

Examples of the “optionally substituted cyclic group” as a substituentof the above-mentioned “optionally substituted C1-C6 alkyl group” or“optionally substituted C2-C6 alkenyl group” for R5 include thosesimilar to the aforementioned “optionally substituted cyclic group” forR5.

The “cyclic group” of the “optionally substituted cyclic group” ispreferably C3-C6 cycloalkyl group, adamantyl group, C6-C14 aryl group, aheterocyclic group or the like.

The “cyclic group” of the “optionally substituted cyclic group”optionally has 1 to 5, preferably 1 to 3, substituents at substitutableposition(s). Examples of such substituent preferably include

(1) halogen,(2) a hydroxy group,(3) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC1-C6 alkoxy group,(4) a C6-C14 aryl group,(5) a C7-C16 aralkyl group,(6) a heterocyclic group,(7) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group,(8) a C1-C6 alkylsulfonyl group,(9) a carboxy group,(10) a C1-C6 alkoxy-carbonyl group,(11) a C1-C6 alkyl-carbonyl group,(12) a heterocyclyl-carbonyl group,and the like.

The “optionally substituted C1-C6 alkyl group” for R5 is preferably aC1-C6 alkyl group optionally substituted by 1 to 3 substituents selectedfrom the group consisting of a hydroxy group, a C1-C6 alkoxy group, aC1-C6 alkylamino group, a carboxy group, a C1-C6 alkoxy-carbonyl group,a C1-C6 alkyl-carbonyl group, a C3-C10 cycloalkyl-carbonyl group, anoptionally substituted C6-C14 aryl-carbonyl group, aheterocyclyl-carbonyl group, a C1-C6 alkyl-carbamoyl group, halogen, anoptionally substituted cyclic group and a C1-C6 alkoxyimino group.

The “optionally substituted C1-C6 alkyl group” for R5 is more preferablya C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of

(1) a hydroxy group,(2) a C1-C6 alkoxy group,(3) a C1-C6 alkylamino group,(4) a carboxy group,(5) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(6) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(7) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(8) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a C1-C6 alkoxy group,(9) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(10) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(11) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(12) an adamantyl group,(13) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen, a hydroxy group and a C1-C6 alkoxy group(e.g., methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like); a C1-C6 alkoxy group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methoxy, ethoxy, trifluoromethoxy andthe like); a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl and thelike); a carboxy group; a C1-C6 alkoxy-carbonyl group (e.g.,methoxycarbonyl and the like); a C1-C6 alkyl-carbonyl group (e.g.,acetyl and the like); a heterocyclyl-carbonyl group (preferably, aheterocyclyl-carbonyl group wherein the heterocyclyl moiety is a 5- or6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., morpholinocarbonyl and the like) and the like,(14) a heterocyclic group (preferably, a 4- to 6-membered (preferably 5-or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, thiazolyl, isoxazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, a hydroxy group and a C1-C6 alkoxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C6-C14 aryl group (e.g., phenyl and the like); a C7-C16 aralkylgroup (e.g., benzyl and the like); a heterocyclic group (preferably, a5- or 6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,(15) a C1-C6 alkoxyimino group (e.g., isopropoxyimino group),and the like.

The “optionally substituted C2-C6 alkenyl group” for R5 is preferably aC2-C6 alkenyl group (e.g., vinyl, allyl, propenyl, isopropenyl,but-3-en-1-yl, pent-4-en-1-yl, hex-5-en-1-yl, 2-methylprop-1-en-1-yl)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a hydroxy group, a C1-C6 alkoxy group, a C1-C6 alkylaminogroup, a carboxy group, a C1-C6 alkoxy-carbonyl group, a C1-C6alkyl-carbonyl group, a C3-C10 cycloalkyl-carbonyl group, an optionallysubstituted C6-C14 aryl-carbonyl group, a heterocyclyl-carbonyl group, aC1-C6 alkyl-carbamoyl group, halogen, an optionally substituted cyclicgroup and a C1-C6 alkoxyimino group.

Examples of the “optionally substituted C1-C6 alkyl group” for R8 or R8′include those similar to the aforementioned “optionally substitutedC1-C6 alkyl” for R5.

Examples of the “optionally substituted cyclic group” for R8 or R8′include those similar to the aforementioned “optionally substitutedcyclic group” for R5.

R8 and R8′ are preferably optionally substituted cyclic groups.

The “cyclic group” of the “optionally substituted cyclic group” for R8or R8′ is preferably a C6-C14 aryl group, a heterocyclic group or thelike.

The “cyclic group” of the “optionally substituted cyclic group” for R8or R8′ optionally has 1 to 5, preferably 1 to 3, substituents atsubstitutable position(s). Examples of such substituent include

(1) halogen,(2) a hydroxy group,(3) an amino group,(4) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC1-C6 alkoxy group,(5) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group,(6) a C1-C6 alkylamino group,(7) a di(C1-C6)alkylamino group,(8) a C1-C6 alkylthio group,(9) a C1-C6 alkylsulfonyl group,(10) a carboxy group,(11) a C1-C6 alkoxy-carbonyl group,(12) a C1-C6 alkyl-carbonyl group and the like.

Examples of the “optionally substituted cyclic group” for R8 preferablyinclude

(1) a C6-C14 aryl group (e.g., phenyl),(2) a heterocyclic group (preferably a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., thienyl, thiazolyl, isoxazolyl, pyrazolyl,1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl,1H-indazolyl, benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl,1H-benzotriazolyl, quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl,tetrahydropyranyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl,preferably, morpholinyl),and the like.

Examples of the group represented by the formula: —CO—R8 preferablyinclude

(1) a C6-C14 aryl (e.g., phenyl)-carbonyl group,(2) a heterocyclyl-carbonyl group (heterocyclyl moiety of theheterocyclyl-carbonyl group is preferably a 5- or 6-memberedheterocyclic group containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, or a fusedheterocyclic group wherein said 5- or 6-membered heterocyclic group iscondensed with benzene ring (e.g., thienyl, thiazolyl, isoxazolyl,pyrazolyl, 1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl,benzo[b]thienyl, 1H-indazolyl, benzimidazolyl, benzo[d]isoxazolyl,benzothiazolyl, 1H-benzotriazolyl, quinolyl, oxetanyl, tetrahydrofuryl,morpholinyl, tetrahydropyranyl, 1,3-benzodioxolyl,2,3-dihydrobenzofuranyl)),and the like.

Examples of the “optionally substituted cyclic group” for R8′ preferablyinclude

(1) a C6-C14 aryl group (e.g., phenyl) optionally having 1 to 3substituents selected from halogen; a C1-C6 alkyl group; and a C1-C6alkoxy group optionally substituted by a hydroxy group,(2) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring (e.g., thienyl, thiazolyl, isoxazolyl, pyrazolyl,1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl,1H-indazolyl, benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl,1H-benzotriazolyl, quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl,tetrahydropyranyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl))optionally substituted by 1 to 3 C1-C6 alkyl groups, and the like.

Examples of the group represented by the formula: —O—R8′ preferablyinclude

(1) a C6-C14 aryl (e.g., phenyl)-oxy group optionally having 1 to 3substituents selected from halogen; a C1-C6 alkyl group; and a C1-C6alkoxy group optionally substituted by hydroxy group,(2) a heterocyclyl-oxy group (preferably, the heterocyclyl moiety of theheterocyclyl-oxy group is a 5- or 6-membered heterocyclic groupcontaining, as a ring-constituting atom besides carbon atom, 1 to 4hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring (e.g., thienyl, thiazolyl, isoxazolyl, pyrazolyl,1,2,4-oxadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl,1H-indazolyl, benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl,1H-benzotriazolyl, quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl,tetrahydropyranyl, 1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl))optionally substituted by 1 to 3 C1-C6 alkyl groups, and the like.

R6 is a monocycle heterocyclic group represented by the formula

wherein Z is O or S(O)n (n is an integer of 0 to 2). Z is preferably Oor S.

While the substitutable position of R6 may be any of ortho, meta andpara, with preference given to ortho position.

The monocycle heterocyclic group for R6 includes the following threetautomers of a′, b′ and c′.

The above-mentioned heterocyclic group (R6) is optionally substituted bya group for R10, as shown below.

As the above-mentioned group for R10, a group represented by the formula—CH(R11)-OCOR12 [wherein R11 is hydrogen, a straight chain or branchedalkyl group having 1 to 6 carbon atoms (e.g., methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,neopentyl and the like), a straight chain or a branched alkenyl grouphaving 2 to 6 carbon atoms or a cycloalkyl group having 3 to 8 carbonatoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl and the like), and R12is a straight chain or a branched alkyl group having 1 to 6 carbon atoms(e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, neopentyl and the like), a straight chainor a branched alkenyl group having 2 to 6 carbon atoms, a cycloalkylgroup having 3 to 8 carbon atoms (e.g., cyclopentyl, cyclohexyl,cycloheptyl and the like), an alkyl group having 1 to 3 carbon atomssubstituted by a cycloalkyl group having 3 to 8 carbon atoms (e.g.,cyclopentyl, cyclohexyl, cycloheptyl and the like) or an optionallysubstituted aryl group having 6 to 14 carbon atoms such as phenyl (e.g.,benzyl, p-chlorobenzyl, phenethyl, cyclopentylmethyl, cyclohexylmethyland the like), an alkenyl group having 2 or 3 carbon atoms substitutedby a cycloalkyl group having 3 to 8 carbon atoms or an optionallysubstituted aryl group having 6 to 14 carbon atoms such as phenyl (e.g.,those having alkenyl moiety such as vinyl, propenyl, allyl, isopropenyland the like (e.g., cinnamyl and the like)), an optionally substitutedaryl group having 6 to 14 carbon atoms such as phenyl (e.g., phenyl,p-tolyl, naphthyl and the like), a straight chain or a branched alkoxygroup having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy,isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy,isopentyloxy, neopentyloxy and the like), a straight chain or a branchedalkenyloxy group having 2 to 8 carbon atoms (e.g., allyloxy,isobutenyloxy and the like), a cycloalkyloxy group having 3 to 8 carbonatoms (e.g., cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and thelike), an alkoxy group having 1 to 3 carbon atoms substituted by acycloalkyl group having 3 to 8 carbon atoms (e.g., cyclopentyl,cyclohexyl, cycloheptyl and the like) or an optionally substituted arylgroup having 6 to 14 carbon atoms such as phenyl (e.g., those havingalkoxy moiety such as methoxy, ethoxy, propoxy, isopropoxy and the like(e.g., benzyloxy, phenethyloxy, cyclopentylmethyloxy,cyclohexylmethyloxy and the like)), an alkenyloxy group having 2 or 3carbon atoms substituted by a cycloalkyl group having 3 to 8 carbonatoms (e.g., cyclopentyl, cyclohexyl, cycloheptyl and the like) or anoptionally substituted aryl group having 6 to 14 carbon atoms such asphenyl (e.g., those having alkenyloxy moiety such as vinyloxy,propenyloxy, allyloxy, isopropenyloxy and the like (e.g., cinnamyloxyand the like)), or an optionally substituted aryloxy group having 6 to14 carbon atoms such as phenoxy (e.g., phenoxy, p-nitrophenoxy,naphthoxy and the like)]; an optionally substituted alkyl group (e.g.,C1-C6 alkyl group); or an acyl group (e.g., C2-C5 alkanoyl group,optionally substituted benzoyl group and the like); and the like can bementioned. Examples of substituent R10 include methyl, ethyl, propyl,tert-butyl, methoxymethyl, triphenylmethyl, cyanoethyl, acetyl,propionyl, pivaloyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl,5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl, acetoxymethyl,propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl,1-(ethoxycarbonyloxy)ethyl, 1-(acetyloxy)ethyl, 1-(isobutyryloxy)ethyl,cyclohexylcarbonyloxymethyl, benzoyloxymethyl, cinnamyl,cyclopentylcarbonyloxymethyl and the like. Such group may be any as longas it is a substituent that is easily converted to the originalheterocyclic group represented by the formula

biologically, or under physiological conditions (e.g., in vivo reactionsuch as oxidation, reduction or hydrolysis and the like by biologicalenzymes and the like), or chemically (what is called a prodrug).

In addition, substituent R6 may further have substituent(s) in additionto the above-mentioned groups for R10. Examples thereof includesubstituents such as an optionally substituted C1-C6 alkyl group (e.g.,methyl, triphenylmethyl and the like), halogen (e.g., F, Cl, Br and thelike), a nitro group, a cyano group, a C1-C6 alkoxy group, an aminogroup, a C1-C6 alkylamino group (e.g., methylamino and the like), adi(C1-C6)alkylamino group (e.g., dimethylamino and the like) and thelike.

R1 is an oxo group; a thioxo group; or a group represented by theformula: ═N—R, ═N—CO—R′, ═N—CO—OR′ or ═N—SO₂—R′.

R is an optionally substituted C1-C6 alkyl group; an optionallysubstituted C3-C6 cycloalkyl group; a group represented by the formula:—O—Ra; or a group represented by the formula: —N(Rb)—Rc.

Ra is hydrogen, an optionally substituted C1-C6 alkyl group or anoptionally substituted C3-C6 cycloalkyl group.

Rb and Rc are each independently hydrogen, an optionally substitutedC1-C6 alkyl group or an optionally substituted C3-C6 cycloalkyl group,or Rb and Rc are bonded to each other to form, together with thenitrogen atom bonded thereto, an optionally substitutednitrogen-containing heterocyclic group.

Examples of the “optionally substituted C1-C6 alkyl group” for R, Ra, Rbor Rc include those similar to the “optionally substituted C1-C6 alkylgroup” for R5. The “optionally substituted C1-C6 alkyl group” for R, Ra,Rb or Rc is preferably a C1-C6 alkyl group.

The “C3-C6 cycloalkyl group” of the “optionally substituted C3-C6cycloalkyl group” for R, Ra, Rb or Rc optionally has 1 to 5, preferably1 to 3, substituent(s) at substitutable position(s). Examples of suchsubstituent include those recited as examples of the substituent of the“optionally substituted cyclic group” for R5. The “optionallysubstituted C3-C6 cycloalkyl group” for R, Ra, Rb or Rc is preferably aC3-C6 cycloalkyl group.

Rb and Rc may be bonded to each other to form, together with thenitrogen atom bonded thereto, an optionally substituted nitrogencontaining heterocyclic group. The “nitrogen containing heterocyclicgroup” is, for example, a 4 to 8-membered (preferably 5- to 7-membered,more preferably 5- or 6-membered) nonaromatic heterocyclic group whichcontains, as a ring-constituting atom besides carbon atom, one nitrogenatom, and may further contain a hetero atom selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom. Preferableexamples of the nitrogen-containing heterocyclic group include1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, 1-pyrazolidinyl,1-piperidinyl, 1-piperazinyl, 4-morpholinyl, 4-thiomorpholinyl,3-thiazolidinyl, 3-oxazolidinyl, 1-azepanyl, 1-azocanyl,1,4-diazepan-1-yl, 1,4-oxazepan-4-yl, 1,4-thiazepan-4-yl and the like.The “nitrogen-containing heterocyclic group” optionally has 1 or 2substituents at substitutable position(s). Examples of the substituentinclude a hydroxy group, an optionally halogenated C1-C6 alkyl group, aC6-C14 aryl group, a C7-C16 aralkyl group, a C1-C6 alkyl-carbonyl group,a C1-C6 alkoxy-carbonyl group and the like.

R′ is an optionally substituted C1-C6 alkyl group or an optionallysubstituted cyclic group.

Examples of the “optionally substituted C1-C6 alkyl group” for R′include those similar to the “optionally substituted C1-C6 alkyl group”for R5. Preferable examples of the “optionally substituted C1-C6 alkylgroup” for R′ include a C1-C6 alkyl group.

Examples of the “optionally substituted cyclic group” for R′ includethose similar to “optionally substituted cyclic group” for R5.Preferable examples of the “optionally substituted cyclic group” for R′include a C6-C14 aryl group.

R1 is preferably an oxo group or a group represented by the formula:═N—SO₂—R′ (R′ is preferably a C1-C6 alkyl group or a C6-C14 aryl group),more preferably an oxo group.

A group represented by the formula:

is preferably

Y is an optionally substituted C1-C4 alkylene group or a grouprepresented by the formula: —O—W—, —W—O—, —N(Rd)-W— or —W—N(Rd)—,wherein W is a bond or an optionally substituted C1-C4 alkylene group,and Rd is an optionally substituted C1-C6 alkyl group or an optionallysubstituted C3-C6 cycloalkyl group.

The “C1-C4 alkylene group” for Y or W may be a straight chain or abranched chain, for example, methylene, ethylene, —(CH₂)₃—, —(CH₂)₄—,—CH(CH₃)—, —C(CH₃)₂—, —CH(CH₃)—CH₂—, —CH₂—CH(CH₃)—, —C(CH₃)₂—CH₂—,—CH₂—C(CH₃)₂— and the like can be mentioned.

The “C1-C4 alkylene group” for Y or W optionally has 1 to 3 substituentsat substitutable position(s). Examples of the substituent includehalogen (e.g., F, Cl, Br and the like), an oxo group, a hydroxy group, anitro group, a cyano group, an optionally halogenated C1-C6 alkoxy group(e.g., methoxy, ethoxy, trifluoromethoxy and the like), an amino group,a C1-C6 alkylamino group (e.g., methylamino and the like), adi(C1-C6)alkylamino group (e.g., dimethylamino and the like), a C1-C6alkyl-carbonylamino group (e.g., acetylamino and the like) and the like.

Examples of the “optionally substituted C1-C6 alkyl group” for Rdinclude those similar to the “optionally substituted C1-C6 alkyl group”for R5. The “optionally substituted C1-C6 alkyl group” for Rd ispreferably a C1-C6 alkyl group.

Examples of the “optionally substituted C3-C6 cycloalkyl group” for Rdinclude those similar to the “optionally substituted C3-C6 cycloalkylgroup” for R. Ra, Rb or Rc. The “optionally substituted C3-C6 cycloalkylgroup” for Rd is preferably a C3-C6 cycloalkyl group.

Y is preferably a C1-C4 alkylene group, more preferably methylene orethylene, and particularly preferably methylene.

In the group represented by the formula:

the biphenyl group may be further optionally substituted. Examples ofthe substituent include 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like), a hydroxy group, anitro group, a cyano group, an optionally halogenated C1-C6 alkyl group(e.g., methyl, ethyl, trifluoromethyl and the like), an optionallyhalogenated C1-C6 alkoxy group (e.g., methoxy, ethoxy, trifluoromethoxyand the like), an amino group, a C1-C6 alkylamino group (e.g.,methylamino and the like), a di(C1-C6)alkylamino group (e.g.,dimethylamino and the like), a C1-C6 alkyl-carbonylamino group (e.g.,acetylamino and the like) and the like.

Preferable examples of the substituent that the biphenyl groupoptionally further has include 1 to 3 substituents selected from thegroup consisting of

(1) halogen (e.g., F, Cl, Br and the like);(2) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); and(3) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and C1-C6 alkoxy, and the like.More preferred is halogen (e.g., F, Cl, Br and the like), and still morepreferred is fluorine.

Preferable examples of R2 represented by the formula

(each symbol is as defined above, and the biphenyl group may be furthersubstituted) are, for example, a group represented by the formula

[wherein

R13 is

(1) hydrogen,(2) halogen (e.g., F, Cl, Br and the like),(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like), or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group,more preferably halogen (e.g., F, Cl, Br and the like),and still more preferably fluorine; andZ is O or S.], and specifically,

and the like are preferable.

Examples of the “optionally substituted C1-C6 alkyl group” for R3 or R4include those similar to the “optionally substituted C1-C6 alkyl group”for R5.

As the “optionally substituted C1-C6 alkyl group” for R3 is preferably aC1-C6 alkyl group optionally substituted by 1 to 3 substituents selectedfrom the group consisting of a C1-C6 alkoxy group, a C3-C6 cycloalkyloxygroup, halogen, a hydroxy group, an oxo group and a C3-C6 cycloalkylgroup, and a C1-C6 alkyl group optionally substituted by 1 to 3substituents selected from the group consisting of a C1-C6 alkoxy group,halogen, a hydroxy group and a C3-C6 cycloalkyl group is morepreferable, and a C1-C6 alkyl group is further more preferable.

The “optionally substituted C1-C6 alkyl group” for R4 is preferably aC1-C6 alkyl group optionally substituted by 1 to 3 substituents selectedfrom the group consisting of a C1-C6 alkoxy group, a C3-C6 cycloalkyloxygroup, a hydroxy group, halogen, a cyclic hydrocarbon group (preferably,a C3-C6 cycloalkyl group or a C6-C14 aryl group), a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, for example, morpholinyl andthe like) and a C1-C6 alkoxy-carbonyl group.

Examples of the “optionally substituted C3-C6 cycloalkyl group” for R3or R4 include those similar to the “optionally substituted C3-C6cycloalkyl group” for R, Ra, Rb or Rc. The “optionally substituted C3-C6cycloalkyl group” for R3 or R4 is preferably a C3-C6 cycloalkyl group.

The “optionally substituted C1-C6 alkoxy group” for R3 or R4 optionallyhas 1 to 5, preferably 1 to 3, substituents at substitutableposition(s). Examples of the substituent include those recited as thesubstituent of the “optionally substituted C1-C6 alkyl group” for R5.The “optionally substituted C1-C6 alkoxy group” for R3 or R4 ispreferably a C1-C6 alkoxy group.

Examples of the “optionally substituted C1-C6 alkylamino group” for R3or R4 include an amino group monosubstituted by “optionally substitutedC1-C6 alkyl group” can be mentioned. Examples of the “optionallysubstituted C1-C6 alkyl group” include those similar to the “optionallysubstituted C1-C6 alkyl group” for R5. The “optionally substituted C1-C6alkylamino group” for R3 or R4 is preferably a C1-C6 alkylamino group.

Examples of the “optionally substituted di(C1-C6)alkylamino group” forR3 or R4 include an amino group disubstituted by “optionally substitutedC1-C6 alkyl group”. Examples of the “optionally substituted C1-C6 alkylgroup” include those similar to the “optionally substituted C1-C6 alkylgroup” for R5. The “optionally substituted di(C1-C6)alkylamino group”for R3 or R4 is preferably a di(C1-C6)alkylamino group.

The “optionally substituted alkylthio group” for R3 or R4 optionally has1 to 5, preferably 1 to 3, substituents at substitutable position(s).Examples of the substituent include those similar to the substituents ofthe “optionally substituted C1-C6 alkyl group” for R5. The “optionallysubstituted alkylthio group” for R3 or R4 is preferably a C1-C6alkylthio group.

As R3,

a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a C3-C6cycloalkyloxy group, halogen, a hydroxy group, an oxo group and a C3-C6cycloalkyl group;

a C3-C6 cycloalkyl group;

a C1-C6 alkoxy group;

a C3-C6 cycloalkyloxy group; or

a C1-C6 alkylthio group is preferable,

a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, halogen, ahydroxy group and a C3-C6 cycloalkyl group;

a C3-C6 cycloalkyl group;

a C1-C6 alkoxy group; or

a C1-C6 alkylthio group is more preferable, and

a C1-C6 alkyl group is further more preferable.

As R4,

hydrogen;

a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a C3-C6cycloalkyloxy group, a hydroxy group, halogen, a cyclic hydrocarbongroup (preferably, a C3-C6 cycloalkyl group or a C6-C14 aryl group), aheterocyclic group (preferably, a 5- or 6-membered, aromatic or anonaromatic heterocyclic group containing, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected fromthe group consisting of nitrogen atom, sulfur atom and oxygen atom, forexample, morpholinyl and the like) and a C1-C6 alkoxy-carbonyl group;

a C3-C6 cycloalkyl group;

a C1-C6 alkoxy group;

a C3-C6 cycloalkyloxy group; or

a di(C1-C6)alkylamino group is preferable, and

a C1-C6 alkyl group is further more preferable.

In the compounds of the present invention, when R1 is an oxo group, andR5 is bonded to a nitrogen atom on the heterocycle and is hydrogen, atautomer shown below may be present.

When R1 is ═N—R, ═N—CO—R′, ═N—CO—OR′ or ═N—SO₂—R′, and R5 is bonded tothe nitrogen atom on the heterocycle and is hydrogen, a tautomer shownbelow can be present.

wherein R1′ is ═N—R, ═N—CO—R′, ═N—CO—OR′ or ═N—SO₂—R′, R1″ is —NH—R,—NH—CO—R′, —NH—CO—OR′ or —NH—SO₂—R′, and R and R′ are as defined above.

These tautomers are also encompassed in the scope of the presentinvention.

Preferable embodiments of a compound represented by the formula (I)include the following compounds.

[Compound A]

A compound represented by the formula:

wherein R3a, R4a and R5a are as defined for R3, R4 and R5, respectively,and other symbols are as defined above, or a salt thereof.

[Compound A-I]

Compound A wherein R3a is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, halogen, ahydroxy group and a C3-C6 cycloalkyl group;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5a is

(1) hydrogen(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a hydroxy group,(ii) a carboxy group,(iii) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(iv) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(v) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(vi) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(vii) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(viii) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(ix) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(x) an adamantyl group,(xi) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen, a hydroxy group and a C1-C6 alkoxy group(e.g., methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like); a C1-C6 alkoxy group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methoxy, ethoxy, trifluoromethoxy andthe like); a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl and thelike); a carboxy group; a C1-C6 alkoxy-carbonyl group (e.g.,methoxycarbonyl and the like); a C1-C6 alkyl-carbonyl group (e.g.,acetyl and the like); a heterocyclyl-carbonyl group (preferably, aheterocyclyl-carbonyl group wherein the heterocyclyl moiety is a 5- or6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., morpholinocarbonyl and the like) and the like,(xii) a heterocyclic group (preferably, a 4- to 6-membered (preferably5- or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, a hydroxy group and a C1-C6 alkoxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C6-C14 aryl group (e.g., phenyl and the like); a C7-C16 aralkylgroup (e.g., benzyl and the like); a heterocyclic group (preferably, a5- or 6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,(xiii) a C1-C6 alkoxyimino group (e.g., isopropoxyimino and the like),and the like;(3) an indanyl group optionally substituted by an oxo group or a hydroxygroup;(4) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like, preferablyphenyl) optionally substituted by 1 to 3 substituents selected from thegroup consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group, a C1-C6alkoxy group and a C1-C6 alkyl-carbonyl group (e.g., methyl, ethyl,isopropyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(vi) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, acyano group, a hydroxy group, a C3-C6 cycloalkyl group, a C1-C6alkoxy-carbonyl group and a carbamoyl group;(vii) a C2-C6 alkenyloxy group (e.g., vinyloxy and the like);(viii) a C2-C6 alkynyloxy group (e.g., 1-methylbut-3-yn-1-yloxy and thelike);(ix) a C3-C10 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, an oxo group, a hydroxy group, a C1-C6 alkyl group, a C1-C6alkoxy group optionally substituted by 1 to 3 halogens, a hydroxy-C1-C6alkyl group and a C1-C6 alkoxy-C1-C6 alkyl group;(x) a C6-C14 aryloxy group (e.g., phenoxy and the like);(xi) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydrofuranyloxy, tetrahydropyranyloxy, piperidinyloxy and the like)optionally substituted by 1 to 3 C1-C6 alkyl groups;(xii) a heterocyclyl-C1-C6 alkyloxy group (preferably, aheterocyclyl-C1-C6 alkyloxy group wherein the heterocyclyl moiety is a5- or 6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., tetrahydropyranylmethoxy and the like);(xiii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(xiv) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(xv) a C1-C6 alkylsulfinyl group (e.g., methylsulfinyl,isopropylsulfinyl and the like);(xvi) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xvii) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xviii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xix) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl and thelike);(xx) a heterocyclic group (preferably, a 5- or 6-membered, aromatic or anonaromatic heterocyclic group containing, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected fromthe group consisting of nitrogen atom, sulfur atom and oxygen atom)(e.g., morpholinyl and the like)and the like;(5) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, pyridyl, dihydrobenzopyranyl,chromenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,tetrahydropyranyl, indolyl and the like) optionally substituted by 1 to3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC1-C6 alkoxy group (e.g., methyl, ethyl, tert-butyl, trifluoromethyl,hydroxymethyl, 1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC3-C6 cycloalkyl group (e.g., methoxy, ethoxy, isopropoxy, neopentyloxy,trifluoromethoxy and the like);(vii) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydropyranyloxy and the like);(viii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(ix) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and the like)and the like;(6) a C2-C6 alkenyl group; or(7) a heterocyclyl-oxy group (preferably, wherein the heterocyclylmoiety of the group is a 5- or 6-membered heterocyclic group containing,as a ring-constituting atom besides carbon atom, 1 to 4 hetero atoms of1 or 2 kinds selected from the group consisting of nitrogen atom, sulfuratom and oxygen atom, or a fused heterocyclic group wherein said 5- or6-membered heterocyclic group is condensed with benzene ring (e.g.,thienyl, thiazolyl, isoxazolyl, pyrazolyl, 1,2,4-oxadiazolyl, pyridyl,pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl, benzimidazolyl,benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl, quinolyl,oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl)) optionally substituted by 1to 3 C1-C6 alkyl groups,

R13 is

(1) hydrogen;(2) halogen (e.g., F, Cl, Br and the like);(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S. Preferably, R3a is

(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, halogen, ahydroxy group and a C3-C6 cycloalkyl group;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5a is

(1) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like, preferablyphenyl) optionally substituted by 1 to 3 substituents selected from thegroup consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group, a C1-C6alkoxy group and a C1-C6 alkyl-carbonyl group (e.g., methyl, ethyl,isopropyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(vi) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, acyano group, a hydroxy group, a C3-C6 cycloalkyl group, a C1-C6alkoxy-carbonyl group and a carbamoyl group;(vii) a C2-C6 alkenyloxy group (e.g., vinyloxy and the like);(viii) a C2-C6 alkynyloxy group (e.g., 1-methylbut-3-yn-1-yloxy and thelike);(ix) a C3-C10 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, an oxo group, a hydroxy group, a C1-C6 alkyl group, a C1-C6alkoxy group optionally substituted by 1 to 3 halogens, a hydroxy-C1-C6alkyl group and a C1-C6 alkoxy-C1-C6 alkyl group;(x) a C6-C14 aryloxy group (e.g., phenoxy and the like);(xi) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydrofuranyloxy, tetrahydropyranyloxy, piperidinyloxy and the like)optionally substituted by 1 to 3 C1-C6 alkyl groups;(xii) a heterocyclyl-C1-C6 alkyloxy group (preferably, aheterocyclyl-C1-C6 alkyloxy group wherein the heterocyclyl moiety is a5- or 6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., tetrahydropyranylmethoxy and the like);(xiii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(xiv) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(xv) a C1-C6 alkylsulfinyl group (e.g., methylsulfinyl,isopropylsulfinyl and the like);(xvi) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xvii) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xviii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xix) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl and thelike);(xx) a heterocyclic group (preferably, a 5- or 6-membered, aromatic or anonaromatic heterocyclic group containing, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected fromthe group consisting of nitrogen atom, sulfur atom and oxygen atom)(e.g., morpholinyl and the like)and the like;(2) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, pyridyl, dihydrobenzopyranyl,chromenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,tetrahydropyranyl, indolyl and the like) optionally substituted by 1 to3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC1-C6 alkoxy group (e.g., methyl, ethyl, tert-butyl, trifluoromethyl,hydroxymethyl, 1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC3-C6 cycloalkyl group (e.g., methoxy, ethoxy, isopropoxy, neopentyloxy,trifluoromethoxy and the like);(vii) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydropyranyloxy and the like);(viii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(ix) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and the like)and the like; or(3) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a hydroxy group,(ii) a carboxy group,(iii) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(iv) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(v) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(vi) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(vii) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(viii) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(ix) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(x) an adamantyl group,(xi) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen, a hydroxy group and a C1-C6 alkoxy group(e.g., methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like); a C1-C6 alkoxy group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methoxy, ethoxy, trifluoromethoxy andthe like); a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl and thelike); a carboxy group; a C1-C6 alkoxy-carbonyl group (e.g.,methoxycarbonyl and the like); a C1-C6 alkyl-carbonyl group (e.g.,acetyl and the like); a heterocyclyl-carbonyl group (preferably, aheterocyclyl-carbonyl group wherein the heterocyclyl moiety is a 5- or6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., morpholinocarbonyl and the like) and the like,(xii) a heterocyclic group (preferably, a 4- to 6-membered (preferably5- or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, a hydroxy group and a C1-C6 alkoxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C6-C14 aryl group (e.g., phenyl and the like); a C7-C16 aralkylgroup (e.g., benzyl and the like); a heterocyclic group (preferably, a5- or 6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,(xiii) a C1-C6 alkoxyimino group (e.g., isopropoxyimino and the like),and the like,

R13 is

(1) hydrogen;(2) halogen (e.g., F, Cl, Br and the like);(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S. [Compound A-II]

Compound A wherein R3a is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, halogen, ahydroxy group and a C3-C6 cycloalkyl group;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5a is

a C6-C14 aryl group (e.g., phenyl, naphthyl and the like, preferablyphenyl) optionally substituted by 1 to 3 substituents selected from thegroup consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group, a C1-C6alkoxy group and a C1-C6 alkyl-carbonyl group (e.g., methyl, ethyl,isopropyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, acyano group, a hydroxy group, a C3-C6 cycloalkyl group, a C1-C6alkoxy-carbonyl group and a carbamoyl group;(vi) a C2-C6 alkenyloxy group (e.g., vinyloxy and the like);(vii) a C2-C6 alkynyloxy group (e.g., 1-methylbut-3-yn-1-yloxy and thelike);(viii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(ix) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(x) a C1-C6 alkylsulfinyl group (e.g., methylsulfinyl, isopropylsulfinyland the like);(xi) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xii) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xiii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xiv) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl and thelike);and the like,

R13 is

(1) hydrogen;(2) halogen (e.g., F, Cl, Br and the like);(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S. [Compound A-IIA]

-   3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 88);-   6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one    (Example 108);-   6-butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 202);-   6-butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 217);-   6-butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 222);-   3-[4-(1-ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 256);-   3-(4-tert-butoxyphenyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 364);-   2-ethyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 377); or-   2-ethyl-3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 444);    or a salt thereof.

[Compound A-III]

Compound A wherein R3a is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, halogen, ahydroxy group and a C3-C6 cycloalkyl group;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5a is

a C6-C14 aryl group (e.g., phenyl, naphthyl and the like, preferablyphenyl) optionally substituted by 1 to 3 substituents selected from thegroup consisting of(i) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(ii) a C3-C10 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, an oxo group, a hydroxy group, a C1-C6 alkyl group, a C1-C6alkoxy group optionally substituted by 1 to 3 halogens, a hydroxy-C1-C6alkyl group and a C1-C6 alkoxy-C1-C6 alkyl group;(iii) a C6-C14 aryloxy group (e.g., phenoxy and the like);(iv) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydrofuranyloxy, tetrahydropyranyloxy, piperidinyloxy and the like)optionally substituted by 1 to 3 C1-C6 alkyl groups;(v) a heterocyclyl-C1-C6 alkyloxy group (preferably, aheterocyclyl-C1-C6 alkyloxy group wherein the heterocyclyl moiety is a5- or 6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., tetrahydropyranylmethoxy and the like);(vi) a heterocyclic group (preferably, a 5- or 6-membered, aromatic or anonaromatic heterocyclic group containing, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected fromthe group consisting of nitrogen atom, sulfur atom and oxygen atom)(e.g., morpholinyl and the like)and the like,

R13 is

(1) hydrogen;(2) halogen (e.g., F, Cl, Br and the like);(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S. [Compound A-IIIA]

-   3-[4-(cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 255);-   3-[4-(cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 265);-   3-[4-(cyclopentyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 319);-   2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]pyrimidin-4(3H)-one    (Example 378);-   2-ethyl-3-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 381);-   2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 414);-   2-ethyl-3-{4-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 415);-   2-ethyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 416);-   3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 417); or-   2-ethyl-3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 422);    or a salt thereof.

[Compound A-IV]

Compound A wherein R3a is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, halogen, ahydroxy group and a C3-C6 cycloalkyl group;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5a is

a heterocyclic group (preferably, a 5- or 6-membered heterocyclic groupcontaining, as a ring-constituting atom besides carbon atom, 1 to 4hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, pyridyl, dihydrobenzopyranyl,chromenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,tetrahydropyranyl, indolyl and the like) optionally substituted by 1 to3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC1-C6 alkoxy group (e.g., methyl, ethyl, tert-butyl, trifluoromethyl,hydroxymethyl, 1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC3-C6 cycloalkyl group (e.g., methoxy, ethoxy, isopropoxy, neopentyloxy,trifluoromethoxy and the like);(vii) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydropyranyloxy and the like);(viii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(ix) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and the like)and the like,

R13 is

(1) hydrogen;(2) halogen (e.g., F, Cl, Br and the like);(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S. [Compound A-IVA]

-   6-butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 112);-   6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 118);-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 128);-   3-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 131);-   3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 144);-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 234);-   2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 235);-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 239); or-   3-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    (Example 275);    or a salt thereof.

[Compound A-V]

Compound A wherein R3a is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, halogen, ahydroxy group and a C3-C6 cycloalkyl group;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5a is

a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a hydroxy group,(ii) a carboxy group,(iii) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(iv) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(v) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(vi) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(vii) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(viii) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(ix) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(x) an adamantyl group,(xi) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen, a hydroxy group and a C1-C6 alkoxy group(e.g., methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like); a C1-C6 alkoxy group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methoxy, ethoxy, trifluoromethoxy andthe like); a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl and thelike); a carboxy group; a C1-C6 alkoxy-carbonyl group (e.g.,methoxycarbonyl and the like); a C1-C6 alkyl-carbonyl group (e.g.,acetyl and the like); a heterocyclyl-carbonyl group (preferably, aheterocyclyl-carbonyl group wherein the heterocyclyl moiety is a 5- or6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., morpholinocarbonyl and the like) and the like,(xii) a heterocyclic group (preferably, a 4- to 6-membered (preferably5- or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, a hydroxy group and a C1-C6 alkoxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C6-C14 aryl group (e.g., phenyl and the like); a C7-C16 aralkylgroup (e.g., benzyl and the like); a heterocyclic group (preferably, a5- or 6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,(xiii) a C1-C6 alkoxyimino group (e.g., isopropoxyimino and the like),and the like,

R13 is

(1) hydrogen;(2) halogen (e.g., F, Cl, Br and the like);(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S. [Compound A-VA]

-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one    (Example 32);-   6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 37);-   3-benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 47);-   6-butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 48);-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one    (Example 50);-   6-butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 58);-   3-(1,3-benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 64);-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    (Example 81);-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-one    (Example 152); or-   6-butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 165);    or a salt thereof.

[Compound A1]

Compound A wherein R3a is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a C3-C6cycloalkyl group and halogen;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a hydroxy group,(ii) a carboxy group,(iii) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(iv) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(v) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(vi) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(vii) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(viii) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(ix) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(x) an adamantyl group,(xi) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C1-C6 alkoxy group optionally substituted by 1 to 3substituents selected from the group consisting of halogen and a hydroxygroup (e.g., methoxy, ethoxy, trifluoromethoxy and the like); a C1-C6alkylsulfonyl group (e.g., methylsulfonyl and the like); a carboxygroup; a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and thelike); a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like); aheterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonyl groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,morpholinocarbonyl and the like)and the like,(xii) a heterocyclic group (preferably, a 4- to 6-membered (preferably5- or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methyl, ethyl, tert-butyl,trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and the like); a C6-C14aryl group (e.g., phenyl and the like); a C7-C16 aralkyl group (e.g.,benzyl and the like); a heterocyclic group (preferably, a 5- or6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,(xiii) a C1-C6 alkoxyimino group (e.g., isopropoxyimino and the like),and the like;(3) an indanyl group optionally substituted by an oxo group or a hydroxygroup;(4) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group, a C1-C6alkoxy group and a C1-C6 alkyl-carbonyl group (e.g., methyl, ethyl,isopropyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(vi) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, acyano group, a hydroxy group, a C3-C6 cycloalkyl group, a C1-C6alkoxy-carbonyl group and a carbamoyl group;(vii) a C2-C6 alkenyloxy group (e.g., vinyloxy and the like);(viii) a C2-C6 alkynyloxy group (e.g., 1-methylbut-3-yn-1-yloxy and thelike);(ix) a C3-C10 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofan oxo group, a hydroxy group, a C1-C6 alkyl group, a hydroxy-C1-C6alkyl group and a C1-C6 alkoxy-C1-C6 alkyl group;(x) a C6-C14 aryloxy group (e.g., phenoxy and the like);(xi) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydrofuranyloxy, tetrahydropyranyloxy, piperidinyloxy and the like)optionally substituted by 1 to 3 C1-C6 alkyl groups;(vxii) a heterocyclyl-C1-C6 alkyloxy group (preferably, aheterocyclyl-C1-C6 alkyloxy group wherein the heterocyclyl moiety is a5- or 6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., tetrahydropyranylmethoxy and the like);(xiii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(xiv) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(xv) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xvi) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xvii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xviii) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl andthe like);(xix) a heterocyclic group (preferably, a 5- or 6-membered, aromatic ora nonaromatic heterocyclic group containing, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected fromthe group consisting of nitrogen atom, sulfur atom and oxygen atom)(e.g., morpholinyl and the like)and the like; or(5) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, pyridyl, dihydrobenzopyranyl,chromenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,tetrahydropyranyl, indolyl and the like) optionally substituted by 1 to3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group (e.g.,methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC3-C6 cycloalkyl group (e.g., methoxy, ethoxy, isopropoxy, neopentyloxy,trifluoromethoxy and the like);(vii) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydropyranyloxy and the like);(viii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(ix) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and the like)and the like,R13 is hydrogen, halogen or C1-C6 alkoxy group, and

Z is O or S. [Compound A2]

Compound A wherein R3a is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a C3-C6cycloalkyl group and halogen;(2) a C3-C6 cycloalkyl group; or(3) a C1-C6 alkoxy group,

R4a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen and a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5a is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a hydroxy group,(ii) a carboxy group,(iii) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(iv) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(v) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(vi) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(vii) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(viii) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(ix) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(x) an adamantyl group,(xi) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C1-C6 alkoxy group optionally substituted by 1 to 3substituents selected from the group consisting of halogen and a hydroxygroup (e.g., methoxy, ethoxy, trifluoromethoxy and the like); a C1-C6alkylsulfonyl group (e.g., methylsulfonyl and the like); a carboxygroup; a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and thelike); a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like); aheterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonyl groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,morpholinocarbonyl and the like)and the like,(xii) a heterocyclic group (preferably, a 4- to 6-membered (preferably5- or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methyl, ethyl, tert-butyl,trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and the like); a C6-C14aryl group (e.g., phenyl and the like); a C7-C16 aralkyl group (e.g.,benzyl and the like); a heterocyclic group (preferably, a 5- or6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,and the like;(3) an indanyl group optionally substituted by an oxo group or a hydroxygroup;(4) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group (e.g.,methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl,hydroxymethyl, 1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(vi) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, tert-butoxy, neopentyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofa C1-C6 alkoxy group, halogen, a hydroxy group, a C3-C6 cycloalkyl groupand a C1-C6 alkoxy-carbonyl group;(vii) a C3-C6 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxyand the like);(viii) a C6-C14 aryloxy group (e.g., phenoxy and the like);(ix) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and the like);(x) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(xi) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xii) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xiii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xiv) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl and thelike)and the like; or(5) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, pyridyl, dihydrobenzopyranyl,chromenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group (e.g.,methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group (e.g.,methoxy, ethoxy, trifluoromethoxy and the like);(vii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(viii) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and thelike)and the like,R13 is hydrogen or halogen, and

Z is O or S. [Compound B]

A compound represented by the formula:

wherein R3b, R4b and R5b are as defined for R3, R4 and R5, respectively,and other symbols are as defined above, or a salt thereof.

[Compound B-I]

Compound B wherein R3b is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, halogen, ahydroxy group and a C3-C6 cycloalkyl group;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4b is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5b is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a hydroxy group,(ii) a carboxy group,(iii) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(iv) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(v) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(vi) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(vii) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(viii) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(ix) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(x) an adamantyl group,(xi) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen, a hydroxy group and a C1-C6 alkoxy group(e.g., methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like); a C1-C6 alkoxy group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methoxy, ethoxy, trifluoromethoxy andthe like); a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl and thelike); a carboxy group; a C1-C6 alkoxy-carbonyl group (e.g.,methoxycarbonyl and the like); a C1-C6 alkyl-carbonyl group (e.g.,acetyl and the like); a heterocyclyl-carbonyl group (preferably, aheterocyclyl-carbonyl group wherein the heterocyclyl moiety is a 5- or6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., morpholinocarbonyl and the like) and the like,(xii) a heterocyclic group (preferably, a 4- to 6-membered (preferably5- or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, a hydroxy group and a C1-C6 alkoxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C6-C14 aryl group (e.g., phenyl and the like); a C7-C16 aralkylgroup (e.g., benzyl and the like); a heterocyclic group (preferably, a5- or 6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,(xiii) a C1-C6 alkoxyimino group (e.g., isopropoxyimino and the like),and the like;(3) an indanyl group optionally substituted by an oxo group or a hydroxygroup;(4) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group, a C1-C6alkoxy group and a C1-C6 alkyl-carbonyl group (e.g., methyl, ethyl,isopropyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(vi) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, acyano group, a hydroxy group, a C3-C6 cycloalkyl group, a C1-C6alkoxy-carbonyl group and a carbamoyl group;(vii) a C2-C6 alkenyloxy group (e.g., vinyloxy and the like);(viii) a C2-C6 alkynyloxy group (e.g., 1-methylbut-3-yn-1-yloxy and thelike);(ix) a C3-C10 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, an oxo group, a hydroxy group, a C1-C6 alkyl group, a C1-C6alkoxy group optionally substituted by 1 to 3 halogens, a hydroxy-C1-C6alkyl group and a C1-C6 alkoxy-C1-C6 alkyl group;(x) a C6-C14 aryloxy group (e.g., phenoxy and the like);(xi) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydrofuranyloxy, tetrahydropyranyloxy, piperidinyloxy and the like)optionally substituted by 1 to 3 C1-C6 alkyl groups;(xii) a heterocyclyl-C1-C6 alkyloxy group (preferably, aheterocyclyl-C1-C6 alkyloxy group wherein the heterocyclyl moiety is a5- or 6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., tetrahydropyranylmethoxy and the like);(xiii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(xiv) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(xv) a C1-C6 alkylsulfinyl group (e.g., methylsulfinyl,isopropylsulfinyl and the like);(xvi) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xvii) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xviii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xix) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl and thelike);(xx) a heterocyclic group (preferably, a 5- or 6-membered, aromatic or anonaromatic heterocyclic group containing, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected fromthe group consisting of nitrogen atom, sulfur atom and oxygen atom)(e.g., morpholinyl and the like)and the like;(5) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, pyridyl, dihydrobenzopyranyl,chromenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,tetrahydropyranyl, indolyl and the like) optionally substituted by 1 to3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group (e.g.,methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC3-C6 cycloalkyl group (e.g., methoxy, ethoxy, isopropoxy, neopentyloxy,trifluoromethoxy and the like);(vii) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydropyranyloxy and the like);(viii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(ix) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and the like)and the like;(6) a C6-C14 aryl (e.g., phenyl)-carbonyl group;(7) a heterocyclyl-carbonyl group (the heterocyclyl moiety of the groupis, preferably, a 5- or 6-membered heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom, or a fused heterocyclic group wherein said 5- or6-membered heterocyclic group is condensed with benzene ring (e.g.,thienyl, thiazolyl, isoxazolyl, pyrazolyl, 1,2,4-oxadiazolyl, pyridyl,pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl, benzimidazolyl,benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl, quinolyl,oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl));(8) a C6-C14 aryl (e.g., phenyl)-oxy group optionally having 1 to 3substituents selected from halogen; a C1-C6 alkyl group; a C1-C6 alkoxygroup optionally substituted by a hydroxy group; or(9) a heterocyclyl-oxy group (preferably, the heterocyclyl moiety of thegroup is a 5- or 6-membered heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom, or a fused heterocyclic group wherein said 5- or6-membered heterocyclic group is condensed with benzene ring (e.g.,thienyl, thiazolyl, isoxazolyl, pyrazolyl, 1,2,4-oxadiazolyl, pyridyl,pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl, benzimidazolyl,benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl, quinolyl,oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,1,3-benzodioxolyl, 2,3-dihydrobenzofuranyl)) optionally substituted by 1to 3 C1-C6 alkyl groups,

R13 is

(1) hydrogen;(2) halogen (e.g., F, Cl, Br and the like);(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S. Preferably, R3b is

(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, halogen, ahydroxy group and a C3-C6 cycloalkyl group;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4b is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5b is

(1) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group, a C1-C6alkoxy group and a C1-C6 alkyl-carbonyl group (e.g., methyl, ethyl,isopropyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(vi) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, acyano group, a hydroxy group, a C3-C6 cycloalkyl group, a C1-C6alkoxy-carbonyl group and a carbamoyl group;(vii) a C2-C6 alkenyloxy group (e.g., vinyloxy and the like);(viii) a C2-C6 alkynyloxy group (e.g., 1-methylbut-3-yn-1-yloxy and thelike);(ix) a C3-C10 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, an oxo group, a hydroxy group, a C1-C6 alkyl group, a C1-C6alkoxy group optionally substituted by 1 to 3 halogens, a hydroxy-C1-C6alkyl group and a C1-C6 alkoxy-C1-C6 alkyl group;(x) a C6-C14 aryloxy group (e.g., phenoxy and the like);(xi) a heterocyclyl-oxy group optionally substituted by 1 to 3 C1-C6alkyl groups (preferably, a heterocyclyl-oxy group wherein theheterocyclyl moiety is a 5- or 6-membered, aromatic or non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms of 1 or 2 kinds selected from the group consistingof nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydrofuranyloxy, tetrahydropyranyloxy, piperidinyloxy and thelike);(xii) a heterocyclyl-C1-C6 alkyloxy group (preferably, aheterocyclyl-C1-C6 alkyloxy group wherein the heterocyclyl moiety is a5- or 6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., tetrahydropyranylmethoxy and the like);(xiii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(xiv) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(xv) a C1-C6 alkylsulfinyl group (e.g., methylsulfinyl,isopropylsulfinyl and the like);(xvi) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xvii) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xviii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xix) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl and thelike);(xix) a heterocyclic group (preferably, a 5- or 6-membered, aromatic ora nonaromatic heterocyclic group containing, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected fromthe group consisting of nitrogen atom, sulfur atom and oxygen atom)(e.g., morpholinyl and the like)and the like;(2) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, pyridyl, dihydrobenzopyranyl,chromenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,tetrahydropyranyl, indolyl and the like) optionally substituted by 1 to3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC1-C6 alkoxy group (e.g., methyl, ethyl, tert-butyl, trifluoromethyl,hydroxymethyl, 1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC3-C6 cycloalkyl group (e.g., methoxy, ethoxy, isopropoxy, neopentyloxy,trifluoromethoxy and the like);(vii) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydropyranyloxy and the like);(viii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(ix) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and the like)and the like; or(3) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a hydroxy group,(ii) a carboxy group,(iii) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(iv) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(v) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(vi) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(vii) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(viii) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(ix) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(x) an adamantyl group,(xi) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen, a hydroxy group and a C1-C6 alkoxy group(e.g., methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like); a C1-C6 alkoxy group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methoxy, ethoxy, trifluoromethoxy andthe like); a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl and thelike); a carboxy group; a C1-C6 alkoxy-carbonyl group (e.g.,methoxycarbonyl and the like); a C1-C6 alkyl-carbonyl group (e.g.,acetyl and the like); a heterocyclyl-carbonyl group (preferably, aheterocyclyl-carbonyl group wherein the heterocyclyl moiety is a 5- or6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., morpholinocarbonyl and the like) and the like,(xii) a heterocyclic group (preferably, a 4- to 6-membered (preferably5- or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen, a hydroxy group and a C1-C6 alkoxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C6-C14 aryl group (e.g., phenyl and the like); a C7-C16 aralkylgroup (e.g., benzyl and the like); a heterocyclic group (preferably, a5- or 6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,(xiii) a C1-C6 alkoxyimino group (e.g., isopropoxyimino and the like),and the like,

R13 is

(1) hydrogen;(2) halogen (e.g., F, Cl, Br and the like);(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S. [Compound B-IA]

-   5-benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 4);-   6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    (Example 7);-   5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    (Example 28);-   5-benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    (Example 287);-   2-butyl-5-[hydroxy(phenyl)methyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 452);-   5-benzoyl-2-butyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    (Example 453);-   6-ethyl-5-(morpholin-4-ylmethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    (Example 455);-   6-ethyl-5-(1-hydroxy-2-methylpropyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    (Example 473b);-   6-ethyl-5-(6-isopropoxypyridin-3-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    (Example 483); or-   6-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    (Example 512);    or a salt thereof.

[Compound B1]

Compound B wherein R3b is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a C3-C6cycloalkyl group and halogen;(2) a C3-C6 cycloalkyl group;(3) a C1-C6 alkoxy group; or(4) a C1-C6 alkylthio group,

R4b is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen, a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group) and a heterocyclic group(preferably, a 5- or 6-membered, aromatic or a nonaromatic heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., morpholinyl and thelike);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5b is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a hydroxy group,(ii) a carboxy group,(iii) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(iv) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(v) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(vi) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(vii) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(viii) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(ix) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(x) an adamantyl group,(xi) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C1-C6 alkoxy group optionally substituted by 1 to 3substituents selected from the group consisting of halogen and a hydroxygroup (e.g., methoxy, ethoxy, trifluoromethoxy and the like); a C1-C6alkylsulfonyl group (e.g., methylsulfonyl and the like); a carboxygroup; a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and thelike); a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like); aheterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonyl groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,morpholinocarbonyl and the like)and the like,(xii) a heterocyclic group (preferably, a 4- to 6-membered (preferably5- or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methyl, ethyl, tert-butyl,trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and the like); a C6-C14aryl group (e.g., phenyl and the like); a C7-C16 aralkyl group (e.g.,benzyl and the like); a heterocyclic group (preferably, a 5- or6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,(xiii) a C1-C6 alkoxyimino group (e.g., isopropoxyimino and the like),and the like;(3) an indanyl group optionally substituted by an oxo group or a hydroxygroup;(4) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group, a C1-C6alkoxy group and a C1-C6 alkyl-carbonyl group (e.g., methyl, ethyl,isopropyl, isobutyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(vi) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, sec-butoxy, tert-butoxy, neopentyloxy and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of a C2-C6 alkynyl group, a C1-C6 alkoxy group, halogen, acyano group, a hydroxy group, a C3-C6 cycloalkyl group, a C1-C6alkoxy-carbonyl group and a carbamoyl group;(vii) a C2-C6 alkenyloxy group (e.g., vinyloxy and the like);(viii) a C2-C6 alkynyloxy group (e.g., 1-methylbut-3-yn-1-yloxy and thelike);(ix) a C3-C10 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, cyclohexyloxy, cycloheptyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofan oxo group, a hydroxy group, a C1-C6 alkyl group, a hydroxy-C1-C6alkyl group and a C1-C6 alkoxy-C1-C6 alkyl group;(x) a C6-C14 aryloxy group (e.g., phenoxy and the like);(xi) a heterocyclyl-oxy group optionally substituted by 1 to 3 C1-C6alkyl groups (preferably, a heterocyclyl-oxy group wherein theheterocyclyl moiety is a 5- or 6-membered, aromatic or non-aromaticheterocycle containing, as a ring-constituting atom besides carbon atom,1 to 4 hetero atoms of 1 or 2 kinds selected from the group consistingof nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydrofuranyloxy, tetrahydropyranyloxy, piperidinyloxy and thelike);(xii) a heterocyclyl-C1-C6 alkyloxy group (preferably, aheterocyclyl-C1-C6 alkyloxy group wherein the heterocyclyl moiety is a5- or 6-membered, aromatic or non-aromatic heterocycle containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., tetrahydropyranylmethoxy and the like);(xiii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(xiv) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(xv) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xvi) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xvii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xviii) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl andthe like);(xix) a heterocyclic group (preferably, a 5- or 6-membered, aromatic ora nonaromatic heterocyclic group containing, as a ring-constituting atombesides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected fromthe group consisting of nitrogen atom, sulfur atom and oxygen atom)(e.g., morpholinyl and the like)and the like; or(5) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, pyridyl, dihydrobenzopyranyl,chromenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl,tetrahydropyranyl, indolyl and the like) optionally substituted by 1 to3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group (e.g.,methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen, a hydroxy group and aC3-C6 cycloalkyl group (e.g., methoxy, ethoxy, isopropoxy, neopentyloxy,trifluoromethoxy and the like);(vii) a heterocyclyl-oxy group (preferably, a heterocyclyl-oxy groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,tetrahydropyranyloxy and the like);(viii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(ix) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and the like)and the like,R13 is hydrogen, halogen or C1-C6 alkoxy group, and

Z is O or S. [Compound B2]

Compound B wherein R3b is(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a C3-C6cycloalkyl group and halogen;(2) a C3-C6 cycloalkyl group; or(3) a C1-C6 alkoxy group,

R4b is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of a C1-C6 alkoxy group, a hydroxygroup, halogen and a cyclic hydrocarbon group (preferably, a C3-C6cycloalkyl group or a C6-C14 aryl group);(3) a C3-C6 cycloalkyl group;(4) a C1-C6 alkoxy group; or(5) a di(C1-C6)alkylamino group,

R5b is

(1) hydrogen;(2) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a hydroxy group,(ii) a carboxy group,(iii) a C1-C6 alkoxy-carbonyl group (e.g., ethoxycarbonyl and the like),(iv) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(v) a C3-C10 cycloalkyl-carbonyl group (e.g., cyclohexylcarbonyl,adamantylcarbonyl and the like),(vi) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(vii) a heterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonylgroup wherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom, for example,morpholinocarbonyl and the like),(viii) a C1-C6 alkyl-carbamoyl group (e.g., tert-butylcarbamoyl and thelike),(ix) a C3-C6 cycloalkyl group (e.g., cyclopropyl, cyclohexyl and thelike),(x) an adamantyl group,(xi) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen (e.g., F, Cl, Br and the like); a C1-C6 alkylgroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methyl, ethyl,tert-butyl, trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and thelike); a C1-C6 alkoxy group optionally substituted by 1 to 3substituents selected from the group consisting of halogen and a hydroxygroup (e.g., methoxy, ethoxy, trifluoromethoxy and the like); a C1-C6alkylsulfonyl group (e.g., methylsulfonyl and the like); a carboxygroup; a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and thelike); a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like); aheterocyclyl-carbonyl group (preferably, a heterocyclyl-carbonyl groupwherein the heterocyclyl moiety is a 5- or 6-membered, aromatic ornon-aromatic heterocycle containing, as a ring-constituting atom besidescarbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selected from the groupconsisting of nitrogen atom, sulfur atom and oxygen atom) (e.g.,morpholinocarbonyl and the like)and the like,(xii) a heterocyclic group (preferably, a 4- to 6-membered (preferably5- or 6-membered) heterocyclic group containing, as a ring-constitutingatom besides carbon atom, 1 to 4 hetero atoms of 1 or 2 kinds selectedfrom the group consisting of nitrogen atom, sulfur atom and oxygen atom,or a fused heterocyclic group wherein said 4- to 6-membered (preferably5- or 6-membered) heterocyclic group is condensed with benzene ring)(e.g., thienyl, isoxazolyl, thiazolyl, pyrazolyl, 1,2,4-oxadiazolyl,pyridyl, pyrimidinyl, pyrazinyl, benzo[b]thienyl, 1H-indazolyl,benzimidazolyl, benzo[d]isoxazolyl, benzothiazolyl, 1H-benzotriazolyl,quinolyl, oxetanyl, tetrahydrofuryl, morpholinyl, tetrahydropyranyl,2,3-dihydrobenzofuranyl and the like) optionally substituted by 1 to 3substituents selected from the group consisting of halogen (e.g., F, Cl,Br and the like); a hydroxy group; a C1-C6 alkyl group optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group (e.g., methyl, ethyl, tert-butyl,trifluoromethyl, hydroxymethyl, 1-hydroxyethyl and the like); a C6-C14aryl group (e.g., phenyl and the like); a C7-C16 aralkyl group (e.g.,benzyl and the like); a heterocyclic group (preferably, a 5- or6-membered aromatic heterocyclic group containing, as aring-constituting atom besides carbon atom, 1 to 4 hetero atoms of 1 or2 kinds selected from the group consisting of nitrogen atom, sulfur atomand oxygen atom) (e.g., thienyl, pyridyl and the like); a C1-C6 alkoxygroup optionally substituted by 1 to 3 substituents selected from thegroup consisting of halogen and a hydroxy group (e.g., methoxy, ethoxy,trifluoromethoxy and the like) and the like,and the like;(3) an indanyl group optionally substituted by an oxo group or a hydroxygroup;(4) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) a hydroxy group;(iii) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group (e.g.,methyl, ethyl, isopropyl, isobutyl, tert-butyl, trifluoromethyl,hydroxymethyl, 1-hydroxyethyl and the like);(iv) a C2-C6 alkenyl group (e.g., vinyl and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofhalogen and a hydroxy group;(v) a C3-C6 cycloalkyl group (e.g., cyclopropyl and the like);(vi) a C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy, isopropoxy,isobutoxy, tert-butoxy, neopentyloxy and the like) optionallysubstituted by 1 to 3 substituents selected from the group consisting ofa C1-C6 alkoxy group, halogen, a hydroxy group, a C3-C6 cycloalkyl groupand a C1-C6 alkoxy-carbonyl group;(vii) a C3-C6 cycloalkyloxy group (e.g., cyclopropyloxy, cyclobutyloxyand the like);(viii) a C6-C14 aryloxy group (e.g., phenoxy and the like);(ix) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and the like);(x) a C1-C6 alkylthio group (e.g., methylthio, isopropylthio and thelike);(xi) a C1-C6 alkylsulfonyl group (e.g., methylsulfonyl,isopropylsulfonyl and the like);(xii) a C1-C6 alkyl-carbonyl group (e.g., acetyl and the like);(xiii) a C1-C6 alkyl-carbamoyl group (e.g., methylcarbamoyl and thelike);(xiv) a di(C1-C6)alkyl-carbamoyl group (e.g., dimethylcarbamoyl and thelike),and the like; or(5) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., furyl, thienyl, pyridyl, dihydrobenzopyranyl,chromenyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of(i) halogen (e.g., F, Cl, Br and the like);(ii) an oxo group;(iii) a hydroxy group;(iv) an amino group;(v) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group (e.g.,methyl, ethyl, tert-butyl, trifluoromethyl, hydroxymethyl,1-hydroxyethyl and the like);(vi) a C1-C6 alkoxy group optionally substituted by 1 to 3 substituentsselected from the group consisting of halogen and a hydroxy group (e.g.,methoxy, ethoxy, trifluoromethoxy and the like);(vii) a C1-C6 alkyl-carbonylamino group (e.g., acetylamino and thelike);(viii) a C1-C6 alkoxy-carbonyl group (e.g., methoxycarbonyl and thelike)and the like,R13 is hydrogen or halogen, and

Z is O or S. [Compound C]

A compound represented by the formula:

wherein R3c and R5c are as defined for R3 and R5, respectively, andother symbols are as defined above, or a salt thereof.

[Compound C—I]

Compound C wherein R3c is a C1-C6 alkyl group,

R5c is

(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(ii) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(iii) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like),(iv) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., tetrahydropyranyl andthe like),and the like;(2) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like, preferablyphenyl); or(3) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., 2,3-dihydrobenzofuranyl and the like) optionallysubstituted by 1 to 3 C1-C6 alkyl groups,

R13 is

(1) hydrogen;(2) halogen (e.g., F, Cl, Br and the like);(3) a C1-C6 alkoxy group (e.g., methoxy, ethoxy and the like); or(4) a C1-C6 alkyl group optionally having 1 to 3 substituents selectedfrom the group consisting of halogen and a C1-C6 alkoxy group, and

Z is O or S. [Compound C1]

Compound C wherein R3c is a C1-C6 alkyl group,

R5c is

(1) a C1-C6 alkyl group optionally substituted by 1 to 3 substituentsselected from the group consisting of(i) a C1-C6 alkyl-carbonyl group (e.g., pivaloyl and the like),(ii) a C6-C14 aryl-carbonyl group (e.g., benzoyl and the like)optionally substituted by 1 to 3 substituents selected from the groupconsisting of halogen and a C1-C6 alkoxy group,(iii) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like),(iv) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom) (e.g., tetrahydropyranyl andthe like)and the like;(2) a C6-C14 aryl group (e.g., phenyl, naphthyl and the like, preferablyphenyl); or(3) a heterocyclic group (preferably, a 5- or 6-membered heterocyclicgroup containing, as a ring-constituting atom besides carbon atom, 1 to4 hetero atoms of 1 or 2 kinds selected from the group consisting ofnitrogen atom, sulfur atom and oxygen atom, or a fused heterocyclicgroup wherein said 5- or 6-membered heterocyclic group is condensed withbenzene ring) (e.g., 2,3-dihydrobenzofuranyl and the like) optionallysubstituted by 1 to 3 C1-C6 alkyl groups,R13 is hydrogen or halogen, and

Z is O or S. [Compound C-IA]

-   3-(4′-{[3-butyl-1-(2,2-dimethylpropyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    (Example 14);-   3-(4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    (Example 136);-   3-(4′-{[3-butyl-5-oxo-1-(2-phenylethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    (Example 180);-   3-{4′-[(3-butyl-1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-yl}-1,2,4-oxadiazol-5(4H)-one    (Example 181);-   3-{4′-[(3-butyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-yl}-1,2,4-oxadiazol-5(4H)-one    (Example 182);-   3-(4′-{[3-butyl-5-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    (Example 183);-   3-[4′-({3-butyl-1-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-yl]-1,2,4-oxadiazol-5(4H)-one    (Example 200);-   3-[4′-({3-butyl-1-[2-(4-methoxyphenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-yl]-1,2,4-oxadiazol-5(4H)-one    (Example 301); or-   3-(4′-{[3-butyl-1-(3,3-dimethyl-2-oxobutyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    (Example 302);    or a salt thereof.

[Compound AA]

(1) A crystalline compound of3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.(2) A crystalline compound of hydrate of3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.(3) A crystalline compound of3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,which has an X-ray powder diffraction analysis pattern with peaks atdiffraction angle: 2θ(°) of 4.64, 5.46, 8.40, 11.10, 12.60, 13.10,14.14, 14.36, 14.60, 15.58, 15.86, 16.24, 16.86, 17.52, 19.26, 19.72,20.00, 20.40, 20.80, 21.12, 21.70.(4) A crystalline compound of hydrate of3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt, which has an X-ray powder diffraction analysis patternwith peaks at diffraction angle: 2θ(°) of 4.46, 6.32, 12.66, 12.84,13.46, 13.74, 16.82, 17.08, 17.82, 17.98, 18.38, 19.70, 20.34, 21.80,22.18, 22.80, 24.08, 25.40, 26.70.

[Compound AB]

(1) A crystalline compound of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.(2) A crystalline compound of hydrate of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.(3) A crystalline compound of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,which has an X-ray powder diffraction analysis pattern with peaks atdiffraction angle: 2θ(°) of 4.60, 8.38, 9.28, 9.66, 10.46, 12.26, 12.86,13.98, 16.92, 17.32, 18.70, 18.94, 19.62, 20.18, 20.98.(4) A crystalline compound of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,which has an X-ray powder diffraction analysis pattern with peaks atdiffraction angle: 2θ(°) of 8.50, 11.86, 12.26, 13.98, 17.14, 18.46,19.04, 19.28, 19.62, 20.16, 20.48, 22.58, 24.60.(5) A crystalline compound of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,which has an X-ray powder diffraction analysis pattern with peaks atdiffraction angle: 2θ(°) of 7.36, 7.66, 11.58, 12.84, 13.28, 13.64,14.50, 15.28, 15.50, 18.38, 18.66, 19.28, 20.20, 20.70, 21.72, 22.14,22.82.(6) A crystalline compound of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,which has an X-ray powder diffraction analysis pattern with peaks atdiffraction angle: 2θ(°) of 8.34, 9.16, 10.64, 11.08, 11.42, 12.42,13.18, 13.88, 14.78, 15.58, 16.28, 17.10, 17.80, 18.56, 18.94, 19.18,20.14, 20.86, 21.56, 22.04, 22.44, 23.14, 23.66, 24.80, 26.18, 27.96,29.16.(7) A crystalline compound of hydrate of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt, which has an X-ray powder diffraction analysis patternwith peaks at diffraction angle: 2θ(°) of 4.32, 8.70, 9.86, 12.76,13.10, 15.48, 18.36, 19.68, 20.62, 21.36, 21.76, 22.04, 22.44, 23.10,24.22, 24.62, 27.94, 28.24.(8) A crystalline compound of hydrate of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt, which has an X-ray powder diffraction analysis patternwith peaks at diffraction angle: 2θ(°) of 6.32, 6.84, 8.90, 14.36,16.64, 17.96, 19.18, 19.94, 21.82, 22.04, 22.90, 23.62, 24.92.

[Compound AC]

(1) A crystalline compound of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.(2) A crystalline compound of hydrate of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.(3) A crystalline compound of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,which has an X-ray powder diffraction analysis pattern with peaks atdiffraction angle: 2θ(°) of 4.76, 6.10, 7.30, 7.86, 8.16, 9.18, 9.60,10.66, 11.28, 11.94, 12.58, 13.34, 14.62, 15.10, 15.46, 16.34, 16.90,17.76, 18.64, 19.34, 20.86, 21.58, 22.42, 24.36, 24.86.(4) A crystalline compound of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,which has an X-ray powder diffraction analysis pattern with peaks atdiffraction angle: 2θ(°) of 4.38, 7.42, 8.90, 9.68, 10.92, 11.24, 11.90,12.56, 12.88, 13.34, 14.06, 14.92, 16.64, 17.30, 17.80, 18.70, 19.08,19.40, 20.36, 20.90, 21.20, 21.50, 21.98, 22.40, 22.72, 22.98, 23.68.(5) A crystalline compound of hydrate of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt, which has an X-ray powder diffraction analysis patternwith peaks at diffraction angle: 2θ(°) of 5.02, 5.36, 9.46, 10.66,11.80, 13.42, 17.06, 17.78, 19.00, 19.18, 20.18, 20.88, 21.38, 23.26,23.78, 25.06, 25.74, 26.06, 26.90, 27.34.

As the salt of a compound represented by the formula (I), apharmacologically acceptable salt and the like can be mentioned.Examples thereof include acid addition salt with an acid such astrifluoroacetic acid, acetic acid, lactic acid, succinic acid, maleicacid, tartaric acid, citric acid, gluconic acid, ascorbic acid, benzoicacid, methanesulfonic acid, p-toluenesulfonic acid, cinnamic acid,fumaric acid, phosphonic acid, hydrochloric acid, nitric acid,hydrobromic acid, hydroiodic acid, sulfamic acid, sulfuric acid and thelike; salt with a metal salt such as sodium, potassium, magnesium,calcium and the like; salt with an organic base such as trimethylamine,triethylamine, pyridine, picoline, N-methylpyrrolidine,N-methylpiperidine, N-methylmorpholine and the like, and the like.

A prodrug of the compound (I) means a compound which is converted to thecompound (I) with a reaction due to an enzyme, a gastric acid, etc.under the physiological condition in the living body, that is, acompound which is converted to the compound (I) with oxidation,reduction, hydrolysis, etc. according to an enzyme; a compound which isconverted to the compound (I) by hydrolysis etc. due to gastric acid,etc. A prodrug of compound (I) may be a compound obtained by subjectingan amino group in compound (I) to an acylation, alkylation orphosphorylation (e.g., a compound obtained by subjecting an amino groupin compound (I) to an eicosanoylation, alanylation,pentylaminocarbonylation,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylation,tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylationand tert-butylation, etc.); a compound obtained by subjecting a hydroxygroup in compound (I) to an acylation, alkylation, phosphorylation orboration (e.g., a compound obtained by subjecting a hydroxy group incompound (I) to an acetylation, palmitoylation, propanoylation,pivaloylation, succinylation, fumarylation, alanylation,dimethylaminomethylcarbonylation, etc.); a compound obtained bysubjecting a carboxyl group in compound (I) to an esterification oramidation (e.g., a compound obtained by subjecting a carboxy group incompound (I) to an ethyl esterification, phenyl esterification,carboxymethyl esterification, dimethylaminomethyl esterification,pivaloyloxymethyl esterification, ethoxycarbonyloxyethyl esterification,phthalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methylesterification, cyclohexyloxycarbonylethyl esterification andmethylamidation, etc.) and the like. Any of these compounds can beproduced from compound (I) by a method known per se.

A prodrug of the compound (I) may also be one which is converted intothe compound (I) under a physiological condition, such as thosedescribed in IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, p. 163-198, 1990, Published by HIROKAWA SHOTEN.

When the compound (I) has isomers such as optical isomer, stereoisomer,positional isomer, rotational isomer and the like, and any isomers andmixture of isomers are encompassed in the compound (I). For example,when the compound (I) has an optical isomer, an optical isomer separatedfrom a racemate is also encompassed in the compound (I). These isomerscan be obtained as independent products by a synthesis means or aseparation means (e.g., concentration, solvent extraction, columnchromatography, recrystallization and the like), and the like known perse.

The compound (I) may be a crystal or an amorphous form. When thecompound (I) is a crystal, both a single crystal and crystal mixturesare encompassed in the compound (I). Crystals can be produced bycrystallization according to crystallization methods known per se.

The compound (I) may be a solvate (e.g., hydrate etc.) or a non-solvate,both of which are encompassed in the compound (I).

The compound (I) may be labeled with an isotope (e.g., ³H, ¹⁴C, ³⁵S,¹²⁵I and the like) and the like.

Deuterium-converted compound wherein ¹H has been converted to ²H(D) arealso encompassed in the compound (I).

Since the compound of the present invention has a strong angiotensin IIantagonistic activity (or inhibitory activity) (particularly, AT1receptor antagonistic activity), the compound of the present inventionis useful as an agent for the prophylaxis or treatment of a disease (ora disease whose onset is promoted) developed by the contraction orgrowth of blood vessels or organ disorder, which expresses via anangiotensin II receptor, or due to the presence of angiotensin II, or afactor induced by the presence of angiotensin II, in mammals (e.g.,human, monkey, cat, pig, horse, bovine, mouse, rat, guinea pig, dog,rabbit etc.).

As such diseases, for example, hypertension (including blood pressurecircadian rhythm abnormality), heart diseases (e.g., cardiachypertrophy, heart failure (e.g., acute heart failure, chronic heartfailure including congestive heart failure, diastolic heart failure,systolic heart failure, ventricular dysfuntion), cardiomyopathy, acutecoronary syndromes, angina pectoris, myocarditis, atrial fibrillation,arrhythmia, tachycardia, myocardial infarction etc.), cerebrovasculardisorders (e.g., asymptomatic cerebrovascular disorder, transientcerebral ischemia, stroke, cerebrovascular dementia, hypertensiveencephalopathy, cerebral infarction etc.), cerebral edema, cerebralcirculatory disorder, recurrence and sequela of cerebrovasculardisorders (e.g., neurotic symptom, psychic symptom, subjective symptom,disorder in daily living activities etc.), ischemic peripheralcirculation disorder, peripheral arterial diseases, venousinsufficiency, progression of cardiac dysfunction after myocardialinfarction (post-myocardial infarction), acute or chronic kidneydiseases (e.g., nephritis, glomerulonephritis including chronicglomerulonephritis, glomerulosclerosis, renal failure, thromboticvasculopathy, diabetic nephropathy, complication of dialysis, organdysfunction including nephropathy by radiation damage etc.),arteriosclerosis including atherosclerosis (e.g., aneurysm, coronaryarteriosclerosis, cerebral arteriosclerosis, peripheral arteriosclerosisetc.), vascular hypertrophy, vascular hypertrophy, restenosis,obliteration or re-obliteration and organ disorders after intervention(e.g., percutaneous transluminal coronary angioplasty, stenting,Coronary artery bypass graft (CABG) surgery, coronary angioscopy,intravascular ultrasound, intracoronary thrombolysis etc.),polycythemia, hypertension, organ disorder and vascular hypertrophyafter transplantation, rejection after transplantation, ocular diseases(e.g., glaucoma, ocular hypertension etc.), thrombosis, multiple organdisorder, endothelial dysfunction, hypertensive tinnitus, othercardiovascular diseases (e.g., deep vein thrombosis, obstructiveperipheral circulatory disorder, arteriosclerosis obliterans,thromboangiitis obliterans, ischemic cerebral circulatory disorder,Raynaud's disease, Buerger's disease etc.), metabolic and/or nutritionaldisorders (e.g., obesity, glucose intolerance, hyperlipidemia,hypercholesterolemia, hypertriglyceridemia, hypoHDL-cholesterolemia,hyperuricacidemia, hyperkalemia, hypernatremia etc.), nerve degenerationdiseases (e.g., Alzheimer's disease, Parkinson's disease, amyotrophiclateral sclerosis, AIDS encephalopathy etc.), central nervous systemdisorders (e.g., disorders such as cerebral hemorrhage, cerebralinfarction etc., and their sequela and complication, head injury, spinalinjury, cerebral edema, sensory malfunction, sensory functionaldisorder, autonomic nervous system disorder, autonomic nervous systemmalfunction, multiple sclerosis etc.), migraine headache, dementia,defects of memory, disorder of consciousness, amnesia, anxiety symptom,catatonic symptom, discomfort mental state, psychopathies (e.g.,depressive psychosis, epilepsy, alcoholism etc.), inflammatory diseases(e.g., arthritis such as rheumatoid arthritis, osteoarthritis,rheumatoid myelitis, periostitis etc.; inflammation after operation andinjury; remission of swelling; pharyngitis; cystitis; pneumonia; atopicdermatitis; inflammatory intestinal diseases such as Crohn's disease,ulcerative colitis etc.; meningitis; inflammatory ocular disease;inflammatory pulmonary disease such as pneumonia, pulmonary silicosis,pulmonary sarcoidosis, pulmonary tuberculosis etc.), allergic diseases(e.g., allergic rhinitis, conjunctivitis, gastrointestinal allergy,pollinosis, anaphylaxis etc.), chronic obstructive pulmonary disease,interstitial pneumonia, pneumocytis carinni pneumonia, collagen diseases(e.g., systemic lupus erythematosus, scleroderma, polyarteritis etc.),hepatic diseases (e.g., hepatitis including chronic hepatitis, hepaticcirrhosis, liver fibrosis, Nonalcoholic fatty liver disease,nonalcoholic steatohepatitis etc.), portal hypertension, digestivesystem disorders (e.g., gastritis, gastric ulcer, gastric cancer,gastric disorder after operation, dyspepsia, esophageal ulcer,pancreatitis, colon polyp, cholelithiasis, hemorrhoidal disease, varicesruptures of esophagus and stomach etc.), blood and/or myelopoieticdiseases (e.g., erythrocytosis, vascular purpura, autoimmune hemolyticanemia, disseminated intravascular coagulation syndrome, multiplemyelopathy etc.), bone diseases (e.g., fracture, refracture,osteoporosis, osteomalacia, bone Paget's disease, sclerosing myelitis,rheumatoid arthritis, osteoarthritis of the knee and joint tissuedysfunction and the like caused by diseases similar to these etc.),solid tumor, tumors (e.g., malignant melanoma, malignant lymphoma,cancer of digestive organs (e.g., stomach, intestine etc.) etc.), cancerand cachexia following cancer, metastasis cancer, endocrinopathy (e.g.,Addison's disease, Cushing's syndrome, pheochromocytoma, primaryaldosteronism etc.), Creutzfeldt-Jakob disease, urinary organ and/ormale genital diseases (e.g., cystitis, prostatic hypertrophy, prostaticcancer, sex infectious disease etc.), female disorders (e.g.,climacteric disorder, gestosis, endometriosis, hysteromyoma, ovariandisease, breast disease, sex infectious disease etc.), disease relatingto environment and occupational factors (e.g., radiation hazard, hazardby ultraviolet, infrared or laser beam, altitude sickness etc.),respiratory diseases (e.g., cold syndrome, pneumonia, asthma, pulmonaryhypertension, pulmonary thrombosis and pulmonary embolism etc.),infectious diseases (e.g., viral infectious diseases withcytomegalovirus, influenza virus, herpes virus etc., rickettsiosis,bacterial infectious disease etc.), toxemias (e.g., sepsis, septicshock, endotoxin shock, Gram-negative sepsis, toxic shock syndromeetc.), otorhinolaryngological diseases (e.g., Meniere's syndrome,tinnitus, dysgeusia, vertigo, disequilibrium, dysphagia etc.), skindiseases (e.g., keloid, hemangioma, psoriasis etc.), intradialytichypotension, myasthenia gravis, systemic diseases such as chronicfatigue syndrome, apnea (e.g., sleep apnea etc.), disorders associatedwith apnea (e.g., hypertension etc.) and the like can be mentioned.

Since the compound of the present invention can maintain a certainantihypertensive action through day and night, the dose and frequencycan be reduced as compared to the administration of a compound otherthan the present invention, and moreover, elevation of blood pressurebefore and after awakening, which is particularly problematic inpatients with hypertension, can be suppressed more effectively.

In addition, long-term suppression of action of angiotensin II by thecompound of the present invention results in the improvement orsuppression of promotion of disorder or abnormality in the biologicalfunction and physiological action, that causes adult disorders andvarious diseases linked with aging and the like, which in turn leads tothe primary and secondary prophylaxis of diseases or clinical conditionscaused thereby or suppression of the progression thereof. As thedisorder or abnormality in the biological function and physiologicalaction, for example, disorder or abnormality in automatic controllingcapability of cerebral circulation and/or renal circulation, disorder ofcirculation (e.g., peripheral, cerebral, microcirculation etc.),disorder of blood-brain-barrier, salt sensitivity, abnormal state ofcoagulation and fibrinolysis system, abnormal state of blood and bloodcell components (e.g., accentuation of platelet aggregation action,malfunction of erythrocyte deformability, accentuation of leukocyteadhesiveness, rise of blood viscosity etc.), production and functionaccentuation of growth factor and cytokines (e.g., PDGF, VEGF, FGF,interleukin, TNF-α, MCP-1 etc.), accentuation of production andinfiltration of inflammatory cells, accentuation of production of freeradical, liposteatosis accentuation, endothelial function disorder,endothelium, cell and organ dysfunction, edema, cell morphogenesischange of smooth muscle etc. (morphogenesis to proliferation type etc.),production and function accentuation of vasoactive substance andthrombosis inducers (e.g., endothelin, thromboxane A₂ etc.), abnormalconstriction of blood vessel etc., metabolic disorder (serum lipidabnormalities, dysglycemia etc.), abnormal growth of cell etc.,angiogenesis (including abnormal vasculogenesis during abnormalcapillary reticular formation in adventitial coat of arterioscleroticlesion) and the like can be mentioned. The compound of the presentinvention can be used as an agent for the primary and secondaryprophylaxis or treatment of organ disorders associated with variousdiseases (e.g., cerebrovascular disorder and organ disorder associatedtherewith, organ disorder associated with cardiovascular disease, organdisorder associated with diabetes, organ disorder after interventionetc.). In particular, since the compound has an activity of inhibitingproteinuria, the compound of the present invention can be used as anagent for protecting kidney.

Therefore, the compound of the present invention can be advantageouslyused when the patients with insulin resistance, impaired glucosetolerance, diabetes or hyperinsulinemia have concurrently developed theabove-mentioned diseases or clinical condition.

The compound of the present invention can be used as insulin sensitizer,agent for enhancing insulin sensitivity, retinoid related receptorfunction regulator, peroxisome proliferator-activated receptor ligand,retinoid X receptor ligand and the like. As used herein, the functionregulator means both agonist and antagonist.

The compound of the present invention has hypoglycemic action,hypolipidemic action, insulin resistance improving action, insulinsensitizing action and peroxisome proliferator-activated receptor(hereinafter sometimes to be abbreviated as PPAR) γ (GenBank AccessionNo. L40904) agonist action. As used herein, PPARγ may form a heterodimerreceptor with retinoid X receptor (hereinafter sometimes to beabbreviated as RXR) α (GenBank Accession No. X52773), RXRβ (GenBankAccession No. M84820) or RXRγ (GenBank Accession No. U38480). Thecompound of the present invention has a selective agonist action onPPARγ.

Since the compound of the present invention normalizes the intracellularinsulin signal transduction mechanism, which mainly causes insulinresistance, thereby reducing insulin resistance and enhancing insulinaction, and has a glucose tolerance improvement action. Therefore, thecompound of the present invention or a salt thereof or a prodrug thereof(containing the compound of the present invention) can be used formammals (e.g., human, monkey, cat, pig, horse, bovine, mouse, rat,guinea pig, dog, rabbit etc.) as an improving agent or an agent for theprophylaxis and/or treatment of the diseases in which insulin resistanceis involved.

The compound of the present invention can be used, for example, as anagent for the prophylaxis or treatment of diabetes (e.g., type 1diabetes, type 2 diabetes, gestational diabetes, obesity type diabetes);an agent for the prophylaxis or treatment of dyslipidemia (e.g.,hypertriglyceridemia, hypercholesterolemia, hypoHDL-emia, postprandialhyperlipemia); an insulin sensitizer; an agent for enhancing insulinsensitivity; an agent for the prophylaxis or treatment of impairedglucose tolerance (IGT); and an agent for preventing progression fromimpaired glucose tolerance to diabetes.

In addition, the compound of the present invention can be used, forexample, as an agent for the prophylaxis or treatment ofhyperinsulinemia, metabolic syndrome, hypertension associated withinsulin resistance, hypertension associated with impaired glucosetolerance, hypertension associated with diabetes (e.g., type II diabetesand the like), hypertension associated with hyperinsulinemia, insulinresistance associated with hypertension, impaired glucose toleranceassociated with hypertension, diabetes associated with hypertension, andhyperinsulinemia associated with hypertension.

Moreover, the compound of the present invention can also be used for thetreatment of patients with diabetes, who shows a normal high bloodpressure value.

The compound of the present invention can be also used as an agent forthe prophylaxis or treatment of, for example, diabetic complications[e.g., neuropathy, nephropathy, retinopathy, cataract, macroangiopathy,osteopenia, diabetic hyperosmolar coma, infectious diseases (e.g.,respiratory infection, urinary tract infection, gastrointestinal tractinfection, skin and soft tissue infection, lower limb infection),diabetic gangrene, xerostomia, lowered sense of hearing, cerebrovasculardisease, peripheral circulatory disturbance], obesity, osteoporosis,cachexia (e.g., cancer cachexia, tuberculous cachexia, diabeticcachexia, hemopathic cachexia, endocrinopathic cachexia, infectiouscachexia, cachexia induced by acquired immunodeficiency syndrome), fattyliver, hepatic cirrhosis, hypertension, polycystic ovary syndrome, renaldiseases (e.g., diabetic nephropathy, glomerular nephritis,glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis,end-stage renal disease), muscular dystrophy, myocardial infarction,angina pectoris, cerebrovascular disease (e.g., cerebral infarction,stroke), insulin resistant syndrome, syndrome X, metabolic syndrome(clinical conditions showing at least three selected fromhypertriglyceridemia, hypo-HDL-cholesterolemia, hypertension, abdominalobesity and impaired glucose tolerance), hyperinsulinemia,hyperinsulinemia-induced sensory disorder, tumor (e.g., leukemia, breastcancer, prostate cancer, skin cancer), irritable bowel syndrome, acuteor chronic diarrhea, inflammatory diseases (e.g., arteriosclerosis(e.g., atherosclerosis etc.), rheumatoid arthritis, spondylitisdeformans, osteoarthritis, lumbago, gout, postoperative or traumaticinflammation, remission of swelling, neuralgia, pharyngolaryngitis,cystitis, hepatitis (including non-alcoholic steatohepatitis),pneumonia, pancreatitis, inflammatory colitis, ulcerative colitis),visceral obesity syndrome and the like.

The compound of the present invention can be used for the improvement ofsymptoms associated with peptic ulcer, acute or chronic gastritis,biliary dyskinesia, cholecystitis or the like, such as abdominal pain,nausea, vomiting, epigastric discomfort and the like.

The compound of the present invention is also used as an agent for theprophylaxis or treatment of inflammatory diseases in which TNF-α isinvolved. Here, the inflammatory diseases in which TNF-α is involvedmeans inflammatory diseases developed by the presence of TNF-α, andtreated by a TNF-α suppressing effect. Examples of such inflammatorydiseases include diabetic complications (e.g., retinopathy, nephropathy,neuropathy, macroangiopathy etc.), rheumatoid arthritis, spondylitisdeformans, osteoarthritis, lumbago, gout, postoperative or traumaticinflammation, swelling, neuralgia, pharyngolaryngitis, cystitis,hepatitis, pneumonia, gastric mucosal injury (including aspirin-inducedgastric mucosal injury) and the like.

The compound of the present invention has an apoptosis inhibitoryactivity, and can be used as an agent for the prophylaxis or treatmentof diseases mediated by promotion of apoptosis. Examples of the diseasesmediated by promotion of apoptosis include viral diseases (e.g., AIDS,fulminant hepatitis etc.), neurodegenerative diseases (e.g., Alzheimer'sdisease, Parkinson's disease, amyotrophic lateral sclerosis, retinitispigmentosa, cerebellar degeneration etc.), myelodysplasia (e.g.,aplastic anemia etc.), ischemic diseases (e.g., myocardial infarction,stroke etc.), hepatic diseases (e.g., alcoholic hepatitis, hepatitis B,hepatitis C etc.), joint diseases (e.g., osteoarthritis etc.),atherosclerosis and the like.

The compound of the present invention can be used for reducing visceralfats, inhibiting accumulation of visceral fats, amelioratingglycometabolism, ameliorating lipid metabolism, ameliorating insulinresistance, inhibiting oxidized LDL production, ameliorating lipoproteinmetabolism, ameliorating coronary artery diseases, preventing ortreating cardiovascular complications, preventing or treating heartfailure complications, lowering blood remnant, preventing or treatinganovulation, preventing or treating hirsutism, preventing or treatinghyperandrogenism, and the like.

The compound of the present invention is also used for the secondaryprevention of various diseases mentioned above (e.g., cardiovascularevent such as myocardial infarction etc.) and suppression of progressionthereof.

For diagnostic criteria of diabetes, Japan Diabetes Society reported newdiagnostic criteria in 1999.

According to this report, diabetes is a condition showing any of afasting blood glucose level (glucose concentration of intravenousplasma) of not less than 126 mg/dl, a 75 g oral glucose tolerance test(75 g OGTT) 2 h level (glucose concentration of intravenous plasma) ofnot less than 200 mg/dl, and a non-fasting blood glucose level (glucoseconcentration of intravenous plasma) of not less than 200 mg/dl. Acondition not falling under the above-mentioned diabetes and differentfrom “a condition showing a fasting blood glucose level (glucoseconcentration of intravenous plasma) of less than 110 mg/dl or a 75 goral glucose tolerance test (75 g OGTT) 2 h level (glucose concentrationof intravenous plasma) of less than 140 mg/dl” (normal type) is called a“borderline type”.

In addition, ADA (American Diabetes Association) reported new diagnosticcriteria of diabetes in 1997 and WHO in 1998.

According to these reports, diabetes is a condition showing a fastingblood glucose level (glucose concentration of intravenous plasma) of notless than 126 mg/dl and a 75 g oral glucose tolerance test 2 h level(glucose concentration of intravenous plasma) of not less than 200mg/dl.

According to the above-mentioned reports, impaired glucose tolerance isa condition showing a fasting blood glucose level (glucose concentrationof intravenous plasma) of less than 126 mg/dl and a 75 g oral glucosetolerance test 2 h level (glucose concentration of intravenous plasma)of not less than 140 mg/dl and less than 200 mg/dl. According to thereport of ADA, a condition showing a fasting blood glucose level(glucose concentration of intravenous plasma) of not less than 110 mg/dland less than 126 mg/dl is called IFG (Impaired Fasting Glucose).According to the report of WHO, among the IFG (Impaired FastingGlucose), a condition showing a 75 g oral glucose tolerance test 2 hlevel (glucose concentration of intravenous plasma) of less than 140mg/dl is called IFG (Impaired Fasting Glycemia).

The compound of the present invention can also be used as an agent forimproving or the prophylaxis or treatment of diabetes, borderline type,impaired glucose tolerance, IFG (Impaired Fasting Glucose) and IFG(Impaired Fasting Glycemia), as determined according to theabove-mentioned new diagnostic criteria, or further, as an agent fortreating hypertension of hypertensive patients having not less than theabove-mentioned diagnostic criteria (e.g., fasting blood sugar level of126 mg/dl). Moreover, the compound of the present invention can preventprogression of borderline type, impaired glucose tolerance, IFG(Impaired Fasting Glucose) or IFG (Impaired Fasting Glycemia) intodiabetes.

The compound of the present invention is effective as a drug for thesuppression or improvement of cardiac dysfunction, progression ofcardiac remodeling and aggravation of conditions in, or a drug for thesuppression of decreased survival rate of, cardiac patients (e.g.,cardiac hypertrophy, acute heart failure, chronic heart failureincluding congestive heart failure, impaired vasodilation,cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation,arrhythmia, tachycardia, myocardial infarction and the like) withdiabetes. In addition, it is effective for the prevention of the onsetof a cardiac disease (e.g., cardiac hypertrophy, acute heart failure,chronic heart failure including congestive heart failure, impairedvasodilation, cardiomyopathy, angina pectoris, myocarditis, atrialfibrillation, arrhythmia, tachycardia, myocardial infarction and thelike) and a cerebrovascular disorder (e.g., asymptomatic cerebrovasculardisorder, transient cerebral ischemic attack, stroke, cerebrovasculardementia, hypertensive encephalopathia, cerebral infarction and thelike) in diabetic patients.

Since the compound of the present invention has an activity ofinhibiting body weight gain, the compound of the present invention canbe used as a body weight gain inhibitor to mammals. Target mammals maybe any mammals of which body weight gain is to be avoided. The mammalsmay have a risk of body weight gain genetically or may be suffering fromlifestyle-related diseases such as diabetes, hypertension and/ordyslipidemia etc. The body weight gain may be caused by excessivefeeding or diet without nutrient balance, or may be derived fromcombination drug, for example, agents for enhancing insulin sensitivityhaving PPARγ-agonistic activity such as troglitazone, rosiglitazone,englitazone, ciglitazone, pioglitazone etc. and the like. In addition,body weight gain may be preliminary to obesity, or may be body weightgain of obesity patients. Here, obesity is defined that BMI (body massindex; body weight (kg)/[height (m)]²) is at least twenty-five forJapanese (criterion by Japan Society for the Study of Obesity), or atleast thirty for westerner (criterion by WHO).

The compound of the present invention is useful as an agent for theprophylaxis or treatment of metabolic syndrome. Because patients withmetabolic syndrome have an extreme high incidence of cardiovasculardiseases as compared to patients with single lifestyle-related diseases,the prophylaxis or treatment of metabolic syndrome is quite important toprevent cardiovascular diseases.

Criteria for diagnosis of metabolic syndrome are announced by WHO in1999, and by NCEP in 2001. According to the criterion of WHO, patientswith at least two of abdominal obesity, dyslipidemia (high serumtriglycerides or low HDL cholesterol) and hypertension in addition tohyperinsulinemia or impaired glucose tolerance are diagnosed asmetabolic syndrome (World Health Organization: Definition, Diagnosis andClassification of Diabetes Mellitus and Its Complications. Part I:Diagnosis and Classification of Diabetes Mellitus, World HealthOrganization, Geneva, 1999). According to the criterion of AdultTreatment Panel III of National Cholesterol Education Program, that isan indicator for managing ischemic heart diseases in the United States,patients with at least three of abdominal obesity, hypertriglyceridemia,hypo-HDL cholesterolemia, hypertension and impaired glucose toleranceare diagnosed as metabolic syndrome (National Cholesterol EducationProgram: Executive Summary of the Third Report of National CholesterolEducation Program (NCEP) Expert Panel on Detection, Evaluation, andTreatment of High Blood Cholesterol in Adults (Adults Treatment PanelIII). The Journal of the American Medical Association, Vol. 285,2486-2497, 2001).

The compound of the present invention can be used for treating patientsof hypertension with metabolic syndrome.

Since the compound of the present invention has an anti-inflammatoryaction, the compound of the present invention can be used as ananti-inflammatory agent for preventing or treating inflammatorydiseases. Examples of inflammatory diseases include inflammatorydiseases due to various diseases such as arthritis (e.g. rheumatoidarthritis, osteoarthritis, rheumatoid myelitis, gouty arthritis,synovitis), asthma, allergic diseases, arteriosclerosis includingatherosclerosis (aneurysm, coronary sclerosis, cerebral arterialsclerosis, peripheral arterial sclerosis etc.), digestive tract diseasesuch as inflammatory intestine disease (e.g. Crohn's disease, ulcerativecolitis), diabetic complication (diabetic neuropathy, diabetic vasculardisorder), atopic dermatitis, chronic obstructive pulmonary disease,systemic lupus erythematosus, visceral inflammatory disease (nephritic,hepatitis), autoimmune hemolytic anemia, psoriasis, nervous degenerativedisease (e.g. Alzheimer's disease, Parkinson's diseases, amyotrophiclateral sclerosis, AIDS encephalopathy), central nervous disorder (e.g.cerebrovascular disorder such as cerebral hemorrhage and cerebralinfarct, head trauma, spinal damage, cerebral edema, multiplesclerosis), meningitis, angina pectoris, myocaridial infarction,congestive heart failure, vascular hypertrophy or occlusion and organdisorder after intervention (percutaneous transluminal coronaryangioplasty, stenting, coronary artery bypass graft, coronaryangioscopy, intravascular ultrasound, intracoronary thrombolysis etc),vascular reocclusion or restenosis after bypass operation, endothelialfunctional disorder, other circulatory disease (intermittentclaudication, obstructive peripheral circulatory disorder,arteriosclerosis obliterans, thromboangiitis obliterans, ischemiccerebral circulatory disorder, Raynaud's disease, Buerger's disease),inflammatory ocular disease, inflammatory pulmonary disease (e.g.chronic pneumonia, silicosis, pulmonary sarcoidosis, pulmonarytuberculosis), endometritis, toxemia (e.g. sepsis, septic shock,endotoxin shock, gram negative sepsis, toxin shock syndrome), cachexia(e.g. cachexia due to infection, carcinomatous cachexia, cachexia due toacquired immunodeficiency syndrome), cancer, Addison's disease,Creutzfeldt-Jakob disease, virus infection (e.g. infection of virus suchas cytomegalovirus, influenza virus, herpes virus etc.), disseminatedintravascular coagulation.

In addition, since the compound of the present invention has ananalgesic action, the compound of the present invention can be also usedas an analgesic agent for preventing or treating pain. Examples of paindiseases include acute pain due to inflammation, pain associated withchronic inflammation, pain associated with acute inflammation, painafter operation (pain of incisional, deep pain, organ pain, chronic painafter operation etc.), muscular pain (muscular pain associated withchronic pain disease, shoulder stiffness etc.), arthralgia, toothache,gnathicarthralgia, headache (migraine, catatonic headache, headacheassociated with fever, headache associated hypertension), organ pain(cardiac pain, angina pain, abdominal pain, renal pain, ureterane pain,bladder pain), pain in obstetrics area (mittelschmerz, dysmenorrheal,labor pain), neuralgia (disc hernia, nerve root pain, neuralgia afterherpes zoster, trigeminal neuralgia), carcinomatous pain, reflexsympathetic atrophy, complex local pain syndrome, and the like. Thecompound of the present invention is effective in alleviate directly andrapidly various pains such as nervous pain, carcinomatous pain andinflammatory pain, and exhibits the particularly excellent analgesiceffect to patients and pathologies in which a pain sense threshold islowered.

The compound of the present invention is particularly useful as ananalgesic agent for pain associated with chronic inflammation or painassociated with hypertension, or as an agent for preventing or treatinginflammatory disease or pain due to (1) arteriosclerosis includingatherosclerosis, (2) vascular hypertrophy, occlusion or organ disorderafter intervention, (3) reocclusion, restenosis or endothelialfunctional disorder after bypass operation, (4) intermittentclaudication, (5) obstructive peripheral circulatory disorder, or (6)arteriosclerosis obliterans.

In one embodiment, since the compound of the present invention has anangiotensin II receptor antagonistic action (particularly an AT1receptor antagonistic action) and a PPAR agonistic action (particularlya selective agonist action on PPARγ), the compound is useful as an agentfor the prophylaxis or treatment of cardiovascular diseases such ashypertension, cardiac disease (cardiac hypertrophy, heart failure,myocardial infarction and the like), arteriosclerosis, kidney disease(diabetic nephropathy, chronic glomerulonephritis and the like), strokeand the like; metabolic diseases such as dyslipidemia, obesity, diabetesand the like; and/or central nervous system diseases such as depression,dementia, Alzheimer's disease and the like.

In further embodiment, the compound of the present invention is usefulas an agent for the prophylaxis or treatment of hypertension, cardiacdisease (cardiac hypertrophy, heart failure, myocardial infarction andthe like), arteriosclerosis, kidney disease (diabetic nephropathy,chronic glomerulonephritis and the like), stroke, dyslipidemia, obesity,diabetes, dementia, Alzheimer's disease and the like.

The content of the compound of the present invention in a pharmaceuticalcomposition is generally about 0.01-about 99.9 wt %, preferably about0.1-about 50 wt %, relative to the entire preparation.

The dose of the compound of the present invention is determined inconsideration of age, body weight, general health condition, sex, diet,administration time, administration method, clearance rate, combinationof drugs, the level of disease for which the patient is under treatmentthen, and other factors.

While the dose varies depending on the target disease, condition,subject of administration, administration method and the like, for oraladministration as a therapeutic agent for essential hypertension inadult, the daily dose of 0.1-600 mg is preferably administered in asingle dose or in 2 or 3 portions.

In addition, since the compound of the present invention is superior insafety, it can be administered for a long period.

The compound of the present invention can be used in combination withpharmaceutical agents such as a therapeutic agent for diabetes, atherapeutic agent for diabetic complications, an anti-hyperlipidemiaagent, a therapeutic agent for cardiovascular disease (e.g. heartfailure, angina pectoris, and like that), an anti-arterioscleroticagent, an anti-hypertensive agent, an anti-obesity agent, a diuretic, anantigout agent, an antithrombotic agent, an anti-inflammatory agent, achemotherapeutic agent, an immunotherapeutic agent, a therapeutic agentfor osteoporosis, an anti-dementia agent, an erectile dysfunctionamelioration agent, a therapeutic agent for urinary incontinence/urinaryfrequency, a therapeutic agent for dysurea and the like (hereinafter tobe abbreviated as a concomitant drug). These concomitant drugs may below-molecular-weight compounds, high-molecular-weight proteins,polypeptides, antibodies, vaccines and the like. In this case, theadministration mode of the compound of the present invention and theconcomitant drug is not particularly restricted, and it is sufficientthat the compound of the present invention and the concomitant drug arecombined in administration. Examples of such administration mode includethe following:

(1) administration of a single preparation obtained by simultaneouslyprocessing the compound of the present invention and the concomitantdrug, (2) simultaneous administration of two kinds of preparations ofthe compound of the present invention and the concomitant drug, whichhave been separately produced, by the same administration route,(3) administration of two kinds of preparations of the compound of thepresent invention and the concomitant drug, which have been separatelyproduced, by the same administration route in a staggered manner, (4)simultaneous administration of two kinds of preparations of the compoundof the present invention and the concomitant drug, which have beenseparately produced, by different administration routes,(5) administration of two kinds of preparations of the compound of thepresent invention and the concomitant drug, which have been separatelyproduced, by different administration routes in a staggered manner(e.g., administration in the order of the compound of the presentinvention and the concomitant drug, or in the reverse order) and thelike. The dose of the concomitant drug can be appropriately determinedbased on the dose clinically employed. The mixing ratio of the compoundof the present invention and the concomitant drug can be appropriatelyselected according to the administration subject, administration route,target disease, condition, combination, and other factors. In caseswhere the administration subject is human, for example, the concomitantdrug may be used in an amount of 0.01 to 100 parts by weight per part byweight of the compound of the present invention.

Examples of other therapeutic agents for diabetes include insulinpreparations (e.g., animal insulin preparations extracted from pancreasof bovine and swine; human insulin preparations genetically synthesizedusing Escherichia coli, yeast; zinc insulin; protamine zinc insulin;fragment or derivative of insulin (e.g., INS-1), oral insulinpreparation), insulin sensitizers (e.g., pioglitazone or a salt thereof(preferably hydrochloride), rosiglitazone or a salt thereof (preferablymaleate), Netoglitazone (MCC-555), Rivoglitazone (CS-011), FK-614,compounds described in WO01/38325, Tesaglitazar (AZ-242), Ragaglitazar(N,N-622), Muraglitazar (BMS-298585), Edaglitazone (BM-13-1258),Metaglidasen (MBX-102), Naveglitazar (LY-519818), MX-6054, LY-510929,AMG131 (T-131) or a salt thereof, THR-0921), α-glucosidase inhibitors(e.g., voglibose, acarbose, miglitol, emiglitate), biguanides (e.g.,phenformin, metformin, buformin or a salt thereof (e.g., hydrochloride,fumarate, succinate)), insulin secretagogues [sulfonylureas (e.g.,tolbutamide, glibenclamide, gliclazide, chlorpropamide, tolazamide,acetohexamide, glyclopyramide, glimepiride, glipizide, glybuzole),repaglinide, nateglinide, mitiglinide or a calcium salt hydratethereof], dipeptidyl peptidase IV inhibitors (e.g., Vidagliptin(LAF237), P32/98, Sitagliptin (MK-431), P93/01, PT-100, Saxagliptin(BMS-477118), T-6666, TS-021), β3 agonists (e.g., AJ-9677), GPR40agonists, GLP-1 receptor agonists [e.g., GLP-1, GLP-1MR agent, N,N-2211,AC-2993 (exendin-4), BIM-51077, Aib(8,35)hGLP-[(7,37)NH₂, cJc-1131],amylin agonists (e.g., pramlintide), phosphotyrosine phosphataseinhibitors (e.g., sodium vanadate), gluconeogenesis inhibitors (e.g.,glycogen phosphorylase inhibitors, glucose-6-phosphatase inhibitors,glucagon antagonists), SGLUT (sodium-glucose cotransporter) inhibitors(e.g., T-1095), 11β-hydroxysteroid dehydrogenase inhibitors (e.g.,BVT-3498), adiponectin or agonists thereof, IKK inhibitors (e.g.,AS-2868), leptin resistance improving drugs, somatostatin receptoragonists (compounds described in WO01/25228, WO03/42204, WO98/44921,WO98/45285, WO99/22735 etc.), glucokinase activators (e.g., Ro-28-1675)and the like.

Examples of the therapeutic agents for diabetic complications includealdose reductase inhibitors (e.g., tolrestat, epalrestat, zenarestat,zopolrestat, minalrestat, fidarestat, CT-112, ranirestat (AS-3201)),neurotrophic factors and enhancers thereof (e.g., NGF, NT-3, BDNF,neurotrophin production/secretion promoting agents described inWO01/14372 (e.g.,4-(4-chlorophenyl)-2-(2-methyl-1-imidazolyl)-5-[3-(2-methylphenoxy)propyl]oxazole)),PKC inhibitors (e.g., ruboxistaurin mesylate), AGE inhibitors (e.g.,ALT946, pimagedine, N-phenacylthiazolium bromide (ALT766), EXO-226,Pyridorin, pyridoxamine), active oxygen scavengers (e.g., thiocticacid), cerebral vasodilators (e.g., tiapride, mexiletine), somatostatinreceptor agonists (e.g., BIM23190), apoptosis signal regulating kinase-1(ASK-1) inhibitors and the like.

Examples of the anti-hyperlipidemia agents include statin compoundswhich are cholesterol synthesis inhibitors (e.g., cerivastatin,pravastatin, simvastatin, lovastatin, atorvastatin, fluvastatin,itavastatin or salts thereof (e.g., sodium salt etc.) etc.), squalenesynthetase inhibitors (e.g. TAK-475 etc.) or fibrate compounds having atriglyceride lowering effect (e.g., bezafibrate, clofibrate, simfibrate,clinofibrate etc.), anion exchange resin (e.g., colestyramine),probucol, nicotinic acid drug (e.g., nicomol, niceritrol), phytosterol(e.g., soysterol, γ-oryzanol), EPA, DHA and the like.

Examples of the anti-arteriosclerotic agents include an acyl-Coenzyme Acholesterol acyltransferase (ACAT) inhibitor (e.g. melinamide,Avasimibe, Eflucimibe etc.) and a lipid rich plaque regressing agent(e.g. compounds described in WO 02/06264, WO 03/059900 etc.) and thelike.

Examples of the anti-hypertensive agents include angiotensin convertingenzyme inhibitors (e.g., captopril, enalapril, delapril etc.),angiotensin II antagonists (e.g., candesartan cilexetil, candesartan,losartan, losartan potassium, eprosartan, valsartan, termisartan,irbesartan, tasosartan, olmesartan, olmesartan medoxomil etc.), calciumantagonists (e.g., manidipine, nifedipine, amlodipine, efonidipine,nicardipine etc.), diuretics, renin inhibitor (e.g., aliskiren etc.),aldosterone antagonists (e.g., spironolactone, eplerenone etc.),β-blocker (e.g., metoprolol, atenolol, propranolol, carvedilol, pindololetc.), vasodilators (e.g., nitrate, soluble guanylate cyclase stimulatoror activator, prostacycline etc.), angiotensin vaccine, clonidine andthe like.

Examples of the therapeutic agents for the pulmonary arterialhypertension include endothelin antagonist (e.g., bosentan, sitaxsentan,etc.), phosphodiesterase 5 inhibitor (e.g., sildenafil, tadalafil,vardenafil, etc), soluble guanylate cyclase stimulator or activator(e.g., BAY58-2667, BAY63-2521, HMR-1766, etc).

Examples of the anti-obesity agents include anti-obesity agents actingon the central nervous system (e.g., dexfenfluramine, fenfluramine,phentermine, sibutramine, amfepramone, dexamphetamine, mazindol,phenylpropanolamine, clobenzorex etc.), MCH receptor antagonists (e.g.,SB-568849; SNAP-7941; compounds described in WO01/82925 and WO01/87834),neuropeptide Y antagonists (e.g., CP-422935), cannabinoid receptorantagonists (e.g., SR-141716, SR-147778), ghrelin antagonists,11β-hydroxysteroid dehydrogenase inhibitors (e.g., BVT-3498), pancreaticlipase inhibitors (e.g., orlistat etc.), β3 agonists (e.g., CL-316243,SR-58611-A, UL-TG-307, SB-226552, AJ-9677, BMS-196085, AZ40140 etc.),peptide anorexiants (e.g., leptin, CNTF (Ciliary Neurotropic Factor)etc.), cholecystokinin agonists (e.g., lintitript, FPL-15849 etc.),feeding deterrent (e.g., P-57) and the like.

Examples of the diuretics include xanthine derivatives (e.g., sodiumsalicylate and theobromine, calcium salicylate and theobromine etc.),thiazide preparations (e.g., ethiazide, cyclopenthiazide,trichloromethiazide, hydrochlorothiazide, hydroflumethiazide,benzylhydrochlorothiazide, penflutizide, polythiazide, methyclothiazideetc.), antialdosterone preparations (e.g., spironolactone, eplerenone,triamterene etc.), carbonate dehydratase inhibitors (e.g., acetazolamideand the like), chlorobenzenesulfonamide preparations (e.g.,chlortalidone, mefruside, indapamide etc.), azosemide, isosorbide,etacrynic acid, piretanide, bumetanide, furosemide and the like.

Examples of the antigout agents include allopurinol, probenecid,colchicine, benzbromarone, febuxostat, citrate and the like.

Examples of the antithrombotic agents include anticoagulating agent[e.g., heparin sodium, heparin potassium, warfarin potassium (warfarin),anti-thrombin drug (e.g., argatroban), activated blood coagulationfactor X inhibitor (e.g., compounds described in WO 2004/048363 etc.)and the like], thrombolytic agent [e.g., tPA, urokinase], antiplateletagent [e.g., aspirin, sulfinpyrazone (Anturan), dipyridamole(Persantin), ticlopidine (Panaldine), cilostazol (Pletal), GPIIb/IIIaantagonist (e.g., ReoPro), clopidogrel etc.], and the like.

Examples of the anti-inflammatory agents include non-steroidalanti-inflammatory agents, such as acetaminophen, fenasetin, ethenzamide,sulpyrine, antipyrine, migrenin, aspirin, mefenamic acid, flufenamicacid, diclofenac sodium, loxoprofen sodium, phenylbutazone,indomethacin, ibuprofen, ketoprofen, naproxen, oxaprozin, flurbiprofen,fenbufen, pranoprofen, floctafenine, epirizol, tiaramide hydrochloride,zaltoprofen, gabexate mesylate, camostat mesylate, ulinastatin,colchicine, probenecid, sulfinpyrazone, benzbromarone, allopurinol,sodium gold thiomalate, sodium hyaluronate, sodium salicylate, morphinehydrochloride, salicylic acid, atropine, scopolamine, morphine,pethidine, levorphanol, ketoprofen, naproxen, oxymorphone and theirsalts etc., and the like.

Examples of the chemotherapeutic agents include alkylating agents (e.g.,cyclophosphamide, ifosfamide etc.), metabolic antagonists (e.g.,methotrexate, 5-fluorouracil etc.), antitumor antibiotics (e.g.,mitomycin, adriamycin etc.), plant-derived antitumor agent (e.g.,vincristine, vindesine, Taxol etc.), cisplatin, carboplatin, etoposideand the like. Of these, Furtulon or NeoFurtulon, which are5-fluorouracil derivatives, and the like are preferable.

Examples of the immunotherapeutic agents include microorganism orbacterial components (e.g., muramyl dipeptide derivative, Picibaniletc.), polysaccharides having immunity potentiating activity (e.g.,lentinan, schizophyllan, krestin etc.), cytokines obtained by geneticengineering techniques (e.g., interferon, interleukin (IL) etc.), colonystimulating factors (e.g., granulocyte colony stimulating factor,erythropoietin etc.) and the like, with preference given to IL-1, IL-2,IL-12 and the like.

Examples of the therapeutic agents for osteoporosis includealfacalcidol, calcitriol, elcatonin, calcitonin salmon, estriol,ipriflavone, pamidronate disodium, alendronate sodium hydrate,incadronate disodium and the like.

Examples of the anti-dementia agents include tacrine, donepezil,rivastigmine, galanthamine and the like.

Examples of the erectile dysfunction amelioration agents includeapomorphine, sildenafil citrate and the like.

Examples of the therapeutic agents for urinary incontinence/urinaryfrequency include flavoxate hydrochloride, oxybutynin hydrochloride,propiverine hydrochloride and the like.

Examples of the therapeutic agents for dysuria include acetylcholineesterase inhibitors (e.g., distigmine) and the like.

Furthermore, drugs having a cachexia-improving action established inanimal models and clinical situations, such as cyclooxygenase inhibitors(e.g., indomethacin etc.) [Cancer Research, Vol. 49, pages 5935-5939,1989], progesterone derivatives (e.g., megestrol acetate) [Journal ofClinical Oncology, Vol. 12, pages 213-225, 1994], glucosteroids (e.g.,dexamethasone etc.), metoclopramide agents, tetrahydrocannabinol agents(publications are all as mentioned above), fat metabolism improvingagents (e.g., eicosapentanoic acid etc.) [British Journal of Cancer,Vol. 68, pages 314-318, 1993], growth hormones, IGF-1, or antibodies toa cachexia-inducing factor such as TNF-α, LIF, IL-6, oncostatin M andthe like, can be used in combination with the compound of the presentinvention.

Furthermore, examples of the concomitant drug include nerve regenerationpromoting drugs (e.g., Y-128, VX853, prosaptide), antidepressants (e.g.,desipramine, amitriptyline, imipramine), antiepileptics (e.g.,lamotrigine), antiarrhythmic agents (e.g., mexiletine), acetylcholinereceptor ligands (e.g., ABT-594), endothelin receptor antagonists (e.g.,ABT-627), monoamine uptake inhibitors (e.g., tramadol), narcoticanalgesics (e.g., morphine), GABA receptor agonists (e.g., gabapentin),α2 receptor agonists (e.g., clonidine), local analgesics (e.g.,capsaicin), antianxiety drugs (e.g., benzodiazepines), dopamine agonists(e.g., apomorphine), midazolam, ketoconazole and the like.

The combination drug preferably includes a diuretic, a calciumantagonists, an aldosterone antagonist, a renin inhibitor, a statincompound, an insulin preparation, an insulin sensitizer, anα-glucosidase inhibitor, a biguanide agent, an insulin secretagogue(preferably sulfonylurea agent) and the like. Particularly, a diureticsuch as hydrochlorothiazide and the like and a calcium antagonists suchas amlodipine and the like and an insulin sensitizer such aspioglitazone hydrochloride and the like are preferable.

The above-mentioned combination drug may be a combination of two or morekinds thereof combined at appropriate ratios.

When the compound of the present invention is used in combination with adrug for combined use, the amount of each drug can be reduced within asafe range in consideration of the opposite effect of these drugs.Particularly, the dose of the insulin sensitizer, insulin secretagogueand biguanide can be reduced from conventional level. As a result, theside effects possibly caused by the combination of these agents can beprevented safely. In addition, the dose of the therapeutic agent fordiabetic complications, anti-hyperlipidemia agent or anti-hypertensiveagent can be reduced and, as a result, the side effects possibly causedby these drugs can be effectively prevented.

Since the compound of the present invention potentiates hypoglycemicactivity of other insulin sensitizers, a combined use of the compound ofthe present invention or a salt thereof or a prodrug thereof(particularly, the compound of the present invention) and other insulinsensitizers (preferably pioglitazone hydrochloride) markedly enhances aprophylactic and/or therapeutic effect against diseases in which insulinresistance is involved, such as type II diabetes and the like.

In the pharmaceutical agent of the present invention, the compound (I)can be administered orally or parenterally as it is or after mixing witha pharmacologically acceptable carrier.

The dosage form of a pharmaceutical agent containing compound (I) of thepresent invention when used for oral administration include tablet(including sugar-coated tablet, film-coated tablet, sublingual tablet,orally disintegrating tablet), pill, granule, powder, capsule (includingsoft capsule, microcapsule), syrup, emulsion, suspension, film (e.g.,orally disintegrating film) and the like, and the dosage form thereoffor parenteral administration is, for example, injection, injectingagent, instillation, suppository and the like. In addition, it iseffective to make a sustained release preparation by combining with asuitable base (e.g., polymer of butyric acid, polymer of glycolic acid,copolymer of butyric acid-glycolic acid, a mixture of polymer of butyricacid and polymer of glycolic acid, polyglycerol fatty acid ester etc.).

As a method to produce the compound (I) in the above-mentioned dosageform, a known production method generally used in the pertinent fieldcan be applied. When the above-mentioned dosage form is produced,suitable amounts of additives such as an excipients, a binder, adisintegrant, a lubricant, a sweetener, a surfactant, a suspendingagent, an emulsifier and the like generally used in the pertinent fieldare appropriately added as necessary, and produced.

When the compound (I) is prepared into a tablet, for example, it can beproduced by adding an excipient, a binder, a disintegrant, a lubricantand the like, and when a pill and a granule are to be prepared, they canbe produced by adding an excipient, a binder, a disintegrant and thelike. When a powder and a capsule are to be prepared, they can beproduced by adding an excipient and the like, and when a syrup is to beprepared, it can be produced by adding a sweetener and the like, andwhen an emulsion or a suspension is to be prepared, it can be producedby adding a suspending agent, a surfactant, an emulsifier and the like.

Examples of the excipient include lactose, sucrose, glucose, starch,saccharose, microcrystalline cellulose, powdered glycyrrhiza, mannitol,sodium hydrogen carbonate, calcium phosphate, calcium sulfate and thelike.

Examples of the binder include 5-10 wt % starch liquid paste, 10-20 wt %gum arabic solution or gelatin solution, 1-5 wt % tragacanth solution,carboxymethyl cellulose solution, sodium alginate solution, glycerin andthe like.

Examples of the disintegrant include starch, calcium carbonate and thelike.

Examples of the lubricant include magnesium stearate, stearic acid,calcium stearate, purified talc and the like.

Examples of the sweetener include glucose, fructose, invert sugar,sorbitol, xylitol, glycerin, simple syrup and the like.

Examples of the surfactant include sodium lauryl sulfate, polysorbate80, sorbitan monofatty acid ester, polyoxyl 40 stearate and the like.

Examples of the suspending agent include gum arabic, sodium alginate,sodium carboxymethyl cellulose, methyl cellulose, bentonite and thelike.

Examples of the emulsifier include gum arabic, tragacanth, gelatin,polysorbate 80 and the like.

Furthermore, when the compound (I) is produced in the above-mentioneddosage form, a suitable amount of a colorant, a preservative, anaromatic, a corrigent, a stabilizer, a thickening agent and the liketypically used in the field of preparation can be added on demand.

When the compound (I) is administered parenterally, it is generallyadministered in the form of a liquid formulation (e.g., injection).While the dose varies depending on the subject of administration, targetorgan, symptom, administration method and the like, it is, for example,about 0.01 mg to about 100 mg, preferably about 0.01 to about 50 mg,more preferably about 0.01 to about 20 mg, in the form of an injection,relative to 1 kg of body weight, which is preferably given byintravenous injection. As the injection, intravenous injection as wellas subcutaneous injection, intracutaneous injection, intramuscularinjection, instillation and the like are mentioned, and as a sustainedrelease preparation, iontophoresis transdermal agent and the like arementioned. Such injections are prepared by methods known per se, or bydissolving, suspending or emulsifying the compound (I) in a sterilizedaqueous solution or oily liquid. As an aqueous solution for injection,physiological saline, isotonic solutions containing glucose or otherauxiliary drugs (e.g., D-sorbitol, D-mannitol, sodium chloride and thelike) and the like can be mentioned, and they can be used in combinationwith suitable solubilizing agents, such as alcohols (e.g., ethanol),polyalcohols (e.g., propylene glycol, polyethylene glycol), nonionicsurfactants (e.g., polysorbate 80, HCO-50) and the like. As an oilyliquid, sesame oil, soybean oil and the like can be mentioned, which maybe used in combination with solubilizing agents such as benzyl benzoate,benzyl alcohol and the like. In addition, buffers (e.g., phosphatebuffer, sodium acetate buffer), soothing agents (e.g., benzalkoniumchloride, procaine hydrochloride and the like), stabilizers (e.g., humanserum albumin, polyethylene glycol and the like), preservatives (e.g.,benzyl alcohol, phenol and the like) and the like may be mixedtherewith. A prepared injection is generally filled in an ampoule.

Production Methods

The production methods of the compound of the present invention areexplained in the following.

In the following Production Methods, unless otherwise specified, thestarting compound is easily commercially available, or can be producedby a method known per se or a method analogous thereto.

Compound (I) of the present invention can be produced, for example, bythe method shown below or a method analogous thereto and the like. Inthe following synthetic methods, the starting compounds may be used inthe form of salt and, as such salt, those exemplified as the salt ofcompound (I) can be used.

While the yield of compound (I) obtained by each of the followingmethods may vary depending on the reaction conditions used, compound (I)can be obtained easily at a high purity from the resultant products by aconventional separation and purification means (recrystallization,column chromatography and the like).

wherein R1, X, X₂ and Y are as defined above, X₃ is carbon or nitrogen,and biphenyl group may further have substituent(s).

In reaction (a), 5-trichloromethyloxadiazole compound (Ia) obtained inthe below-mentioned reaction (d) is reacted in the presence of anaqueous alkaline solution to give oxadiazolone compound (Ib). Generally,the reaction is performed in an inert solvent using about 1 to 3 molarequivalents of the aqueous alkaline solution relative to compound (Ia).

Examples of the inert solvent for reaction include ethers such as1,4-dioxane, tetrahydrofuran and the like; alcohols such as methanol,ethanol and the like; water and the like. These solvents may be used asa mixture of two or more kinds thereof at an appropriate ratio.

Examples of the alkali to be used for alkaline aqueous solution includesodium hydroxide, potassium hydroxide, lithium hydroxide, sodiumcarbonate, potassium carbonate and the like.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about 0° C. to about 60° C.

The reaction time is generally about 0.5 to about 20 hr.

wherein R1, X, X₂, X₃ and Y are as defined above, and biphenyl group mayfurther have substituent(s).

In reaction (b), cyano compound (II) obtained in the below-mentionedreactions (d) to (g) is converted to amidoxime compound (III), which isthen subjected to ring closure to give oxadiazolone compound (Ib).

The reaction to obtain compound (III) is performed in an inert organicsolvent using about 1 to 20 mol of hydroxylamine per 1 mol of compound(II).

Examples of such solvent include sulfoxides such as dimethyl sulfoxideand the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; alcohols such as methanol, ethanoland the like; ethers such as 1,4-dioxane, tetrahydrofuran etc. and thelike. These solvents may be used as a mixture of two or more kindsthereof at an appropriate ratio.

When an inorganic acid salt such as hydroxylamine hydrochloride,hydroxylamine sulfate and the like, or an organic acid salt such ashydroxylamine oxalate and the like is used as hydroxylamine, thereaction is performed in the presence of an equivalent amount or a smallexcess of a suitable base such as potassium carbonate, sodium hydrogencarbonate, sodium hydroxide, triethylamine, sodium methoxide, sodiumhydride and the like.

When an inorganic acid salt or organic acid salt of hydroxylamine isused, the reaction may be performed with addition of about 5 to 20 wt %of water to an organic solvent.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about 25° C. to about 100° C.

The reaction time is generally about 3 to about 48 hr.

The reaction to obtain oxadiazolone compound (Ib) from amidoximecompound (III) is performed using about 1 to 2 molar equivalents of acarbonylation reagent relative to amidoxime compound (III) in a solventthat does not adversely influence the reaction in the presence of anequivalent amount or a small excess of a base.

Examples of the carbonylation reagent include N,N′-carbonyldiimidazole,triphosgene, methyl chlorocarbonate, ethyl chlorocarbonate and the like.

Examples of the base include organic amines such as triethylamine,pyridine, diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene andthe like; inorganic salts such as potassium carbonate, sodium carbonateetc. and the like.

Examples of the solvent include halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride and the like; amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide and the like;ethers such as diethyl ether, 1,4-dioxane, tetrahydrofuran etc. and thelike. These solvents may be used as a mixture of two or more kindsthereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 100° C.,preferably about 0° C. to about 50° C.

The reaction time is generally about 0.1 to about 5 hr.

wherein R1, X, X₂, X₃ and Y are as defined above, and biphenyl group mayfurther have substituent(s).

In reaction (c), amidoxime compound (III) obtained in reaction (b) issubjected to ring closure to give thiadiazolone compound (Ic).

The reaction to obtain compound (Ic) is performed using about 1 to 2 molof 1,1′-thiocarbonyldiimidazole per 1 mol of compound (III) in thepresence of Lewis acid in an organic solvent that does not adverselyinfluence the reaction.

The Lewis acid is not particularly limited as long as the reactionproceeds and, for example, boron trifluoride diethyl ether complex,tin(II) chloride, zinc chloride, copper(I) chloride, silica gel and thelike can be mentioned. The amount of the Lewis acids to be used ispreferably about 1 to 3 mol per 1 mol of compound (III).

Examples of the solvent include halogenated hydrocarbons such asdichloromethane, chloroform, carbon tetrachloride and the like; amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide and the like;dimethyl sulfoxide and the like; ethers such as diethyl ether,1,4-dioxane, tetrahydrofuran etc. and the like. These solvents may beused as a mixture of two or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 100° C.,preferably about 0° C. to about 50° C.

The reaction time is generally about 0.1 to about 5 hr.

wherein R1, X and X₂ are as defined above, R7 is a cyano group or a5-trichloromethyl-1,2,4-oxadiazol-3-yl group, E1 is a leaving group(e.g., halogen atom such as chlorine, bromine, iodine and the like;substituted sulfonic acid ester such as methanesulfonic acid ester,p-toluenesulfonic acid ester and the like; hydroxy group and the like),and biphenyl group may further have substituent(s).

In reaction (d), compound (IV) is reacted with compound (v) to give,from among the starting compounds (Ia) to be used in the above-mentionedreaction (a), compound (Iab) wherein X₃ is nitrogen or, from among thestarting compounds (II) to be used in the above-mentioned reaction (b),compound (IIa) wherein X₃ is nitrogen. Generally, the reaction isperformed using 1 to 3 mol of compound (V) per 1 mol of compound (IV) inan organic solvent that does not adversely influence the reaction.

The starting compound (V) to be used in the above-mentioned reaction (d)can be produced by a method known per se, for example, the methoddescribed in U.S. Pat. No. 5,243,054 (JP-A-5-271228) or a methodanalogous thereto.

In reaction (d), when E1 is halogen atom or substituted sulfonic acidester, the reaction is performed according to a conventional method in asolvent that does not adversely influence the reaction in the presenceof base.

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide etc. and the like.

The amount of the bases to be used is preferably about 1 to about 5molar equivalents relative to compound (IV).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; nitrites such as acetonitrile, propionitrile and the like; etherssuch as tetrahydrofuran, 1,4-dioxane, diethyl ether and the like;ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide etc. and the like. These solvents may be used as a mixture oftwo or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 20 hr.

In reaction (d), when E1 is a hydroxy group, this reaction is performedby a method known per se, for example, the method described inSynthesis, p. 1 (1981) and the like or a method analogous thereto. Thatis, this reaction is generally performed in the presence of an organicphosphorus compound and an azo reagent, in a solvent that does notadversely influence the reaction.

Examples of the organic phosphorus compound include triphenylphosphine,tri(n-butyl)phosphine and the like.

Examples of the azo reagent include diethyl azodicarboxylate,diisopropyl azodicarboxylate, 1,1′-(azodicarbonyl)dipiperidine and thelike.

The amount of the organic phosphorus compound and azo reagent to be usedis preferably about 1 to about 5 molar equivalents relative to compound(IV).

Examples of the solvent that does not adversely influence the reactioninclude ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide and the like, and the like. These solventsmay be used as a mixture of two or more kinds thereof at an appropriateratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 20 hr.

wherein R1, X, X₃ and R5 are as defined above, and E2 is a leaving group(e.g., a halogen atom such as chlorine, bromine, iodine and the like; asubstituted sulfonic acid ester such as methanesulfonic acid ester,p-toluenesulfonic acid ester and the like; boronic acid or a boronicacid ester; a hydroxy group and the like). The biphenyl group mayfurther have substituent(s).

In reaction (e), compound (VI) is reacted with compound (VII) to givecompound (IIb), which is starting compound (II) (used in theabove-mentioned reaction (b)) wherein X₂ is a N—R5 group. The reactionis generally performed using 1 to 4 molar equivalents of compound (VII)relative to starting compound (VI).

The starting compound (VI) to be used in the above-mentioned reaction(e) can be produced by a method known per se, for example, the methoddescribed in Journal of Medicinal Chemistry, vol. 37, p. 2371 (1994) ora method analogous thereto.

When E2 is a halogen atom, a substituted sulfonic acid ester or ahydroxy group, the above-mentioned reaction (e) can be performed by amethod similar to the method shown in reaction (d).

Particularly when E2 is a halogen atom or a substituted sulfonic acidester, and R5 is an aryl group, reaction (e) can be also promoted by amethod known per se, for example, the method described in Journal of theAmerican Chemical Society, vol. 124, p. 7421 (2002) and the like or amethod analogous thereto, in the presence of a metal catalyst. Examplesof the metal catalyst include palladium complexes (e.g., palladiumacetate, palladium chloride, tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and the like),copper compounds (e.g., copper powder, copper(I) chloride, copper(I)iodide, copper(I) acetate and the like), nickel compounds (e.g.,tetrakis(triphenylphosphine)nickel and the like), rhodium compounds(e.g., tris(triphenylphosphine)rhodium chloride and the like), platinumcompounds and the like.

The amount of the metal catalyst to be used is about 0.000001 to 5 molarequivalents, preferably 0.0001 to 1 molar equivalent, relative tocompound (VII).

The above-mentioned reaction may be performed using a base and a ligand.Examples of the base include metal alkoxides such as potassiumphenoxide, sodium tert-butoxide and the like; inorganic salts such aspotassium carbonate, sodium carbonate, cesium carbonate, potassiumphosphate etc., and the like. Examples of the ligand include organicphosphorus compounds such as triphenylphosphine,tri-tert-butylphosphine, tricyclohexylphosphine, BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and the like; organicamine compounds such as N,N′-dimethyl-cyclohexane-1,2-diamine,2,2′-bipyridyl and the like, and the like.

When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen and thelike) atmosphere.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 20 hr.

In reaction (e), when E2 is a boronic acid or a boronic acid ester, thisreaction is performed by a method known per se, for example, the methoddescribed in Tetrahedron Letters, vol. 39, p. 2933 (1998) and the likeor a method analogous thereto, in the presence of a base and a metalcatalyst, in a solvent that does not adversely influence the reaction.

Examples of the base include inorganic salts such as potassiumcarbonate, sodium carbonate, cesium carbonate and the like; metalalkoxides such as sodium methoxide, sodium ethoxide, potassiumtert-butoxide and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene etc. and thelike. These bases may be used as a mixture of two or more kinds thereofat an appropriate ratio.

Examples of the metal catalyst include copper or salts thereof (e.g.,copper(II) acetate, copper(II) chloride and the like), palladiumcomplexes (e.g., palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and the like),nickel compounds (e.g., tetrakis(triphenylphosphine)nickel and thelike), rhodium compounds (e.g., tris(triphenylphosphine)rhodium chlorideand the like), platinum compounds and the like. Of these, copper orsalts thereof is preferable.

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether and thelike; ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide etc. and the like. These solvents may be used as a mixture oftwo or more kinds thereof at an appropriate ratio.

When copper or a salt thereof is used as a metal catalyst, this reactionis preferably performed under an air atmosphere or an oxygen atmosphere.When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen and thelike) atmosphere. In addition, this reaction may be performed usingmolecular sieves.

The amount of the metal catalyst to be used is about 0.000001 to 5 molarequivalents, preferably 0.0001 to 1 molar equivalent, relative tocompound (VII).

The reaction temperature is generally about 0° C. to about 200° C.,preferably 10° C. to about 100° C.

The reaction time is generally about 2 to about 96 hr.

wherein R1, X, Y and R5 are as defined above, E3 is a leaving group(e.g., a halogen atom such as chlorine, bromine, iodine etc. and thelike), and M is a metal (e.g., potassium, sodium, lithium, magnesium,copper, mercury, zinc, thallium, boron, tin and the like, they may forma complex). The biphenyl group may further have substituent(s).

In reaction (f), the leaving group E3 is introduced into compound (VIII)to give compound (IX), which is then reacted with compound (X) to givecompound (IIc), which is starting compound (II) (used in theaforementioned reaction (b)) wherein X₂ is a C—R5 group.

The starting compound (VIII) to be used in the above-mentioned reaction(f) can be produced by the method shown in reaction (d) or a methodanalogous thereto.

In the above-mentioned reaction (f), the reaction to obtain compound(IX) from compound (VIII) is performed by a method known per se, forexample, the method described in Journal of the Chemical Society, vol.37, p. 3478 and the like or a method analogous thereto, using ahalogenating agent (e.g., chlorine, bromine, iodine, halogenatedsuccinimide, dihalogenated barbituric acid and the like). The amount ofthe halogenating agent to be used is preferably about 1 to about 5 molarequivalents relative to compound (VIII).

In the above-mentioned reaction (f), the reaction to obtain compound(IX) from compound (VIII) is performed in a solvent that does notadversely influence the reaction. Examples of the solvent includealcohols (e.g., methanol, ethanol, ethylene glycol and the like),halogenated hydrocarbons (e.g., dichloromethane, chloroform and thelike), organic acids (e.g., acetic acid, formic acid and the like) andthe like. These solvents may be used as a mixture of two or more kindsthereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 20 hr.

Compound (X) to be used in the above-mentioned reaction (f) can beproduced according to a method known per se or a method analogousthereto. The amount of compound (X) to be used is preferably about 1 toabout 5 molar equivalents relative to compound (IX).

In the above-mentioned reaction (f), the reaction to obtain compound(IIc) from compound (IX) and compound (X) is performed in a solvent thatdoes not adversely influence the reaction. Preferable examples of suchsolvent include alcohols (e.g., methanol, ethanol, ethylene glycol andthe like), ethers (e.g., diethyl ether, tetrahydrofuran, 1,4-dioxane,1,2-dimethoxyethane and the like), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone and the like), aromatichydrocarbons (e.g., toluene, xylene and the like) and the like. Thesesolvents may be used as a mixture of two or more kinds thereof at anappropriate ratio. Furthermore, water may be mixed with theabove-mentioned solvent at an appropriate ratio.

In the above-mentioned reaction (f), the reaction to obtain compound(IIc) from compound (IX) and compound (X) can be generally promotedusing a metal catalyst. Examples of the metal catalyst include variousmetal complex having a ligand, for example, palladium compounds (e.g.,palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and the like),nickel compounds (e.g., tetrakis(triphenylphosphine)nickel and thelike), rhodium compounds (e.g., tris(triphenylphosphine)rhodium chlorideand the like), platinum compounds and the like. Of these, palladiumcompounds are preferable. The amount of the metal catalyst to be used isabout 0.000001 to 5 molar equivalents, preferably 0.0001 to 1 molarequivalent, relative to compound (IX). When a metal catalyst unstable tooxygen is used, this reaction is preferably performed under an inert gas(e.g., argon, nitrogen and the like) atmosphere.

In the above-mentioned reaction (f), the reaction to obtain compound(IIc) from compound (IX) and compound (X) may be performed using aninorganic salt. Examples of the inorganic salt include potassiumcarbonate, sodium carbonate, cesium carbonate, potassium phosphate,lithium chloride, sodium chloride and the like. The amount of theinorganic salt to be used is preferably about 1 to about 10 molarequivalents relative to compound (IX).

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 24 hr.

wherein X, X₂, X₃, Y and R are as defined above, and biphenyl group mayfurther have substituent(s).

In reaction (g), compound (XI) is reacted with compound (XII) in thepresence of a base to give compound (IId), which is starting compound(II) (used in the above-mentioned reaction (b)) wherein R1 is ═N—Rgroup. Generally, the amount of compound (XII) to be used is preferablyabout 1 to about 5 molar equivalents relative to compound (XI).

Examples of the base include alkali metal salts such as sodium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate andthe like; amines such as pyridine, N,N-diisopropylethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene etc. and thelike. The amount of the base to be used is preferably about 1 to about 5molar equivalents relative to compound (XI).

The starting compound (XI) to be used in the above-mentioned reaction(g) can be produced by a method known per se, for example, the methoddescribed in Journal of Medicinal Chemistry, vol. 37, p. 2371 (1994) ora method analogous thereto. Compound (XII) to be used in theabove-mentioned reaction (g) can be produced according to a method knownper se or a method analogous thereto.

The above-mentioned reaction (g) is performed in a solvent that does notadversely influence the reaction. Preferable examples of such solventinclude ethers (e.g., tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethaneand the like), amides (e.g., N,N-dimethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone and the like), aromatichydrocarbons (e.g., toluene, xylene and the like) and the like.

The reaction temperature is generally about −50° C. to about 250° C.,preferably about 50° C. to about 170° C.

The reaction time is generally about 0.5 to about 48 hr.

wherein X, X₂, X₃, Y, R1 and R6 are as defined above, one of R90 and R91is a leaving group (e.g., a halogen atom such as chlorine, bromine,iodine and the like; a substituted sulfonic acid ester such astrifluoromethanesulfonic acid ester, methanesulfonic acid ester,p-toluenesulfonic acid ester and the like; a hydroxy group and thelike), and the other is a metal (e.g., potassium, sodium, lithium,magnesium, copper, mercury, zinc, thallium, boron, tin and the like).

In the above-mentioned reaction (h), compound (XIII) is reacted withcompound (XIV) to give compound (Id).

The reaction to obtain compound (Id) is performed using 1 to 3 mol ofcompound (XIV) per 1 mol of compound (XIII) in an organic solvent thatdoes not adversely influence the reaction.

Examples of the solvent include alcohols such as methanol, ethanol,ethylene glycol and the like; ethers such as diethyl ether,tetrahydrofuran, 1,4-dioxane and the like; halogenated hydrocarbons suchas chloroform, dichloromethane and the like; aromatic hydrocarbons suchas benzene, toluene, xylene and the like; amides such asN,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide etc. and the like. These solvents may be used as a mixture oftwo or more kinds thereof at an appropriate ratio. Furthermore, watermay be mixed with the above-mentioned solvent at an appropriate ratio.

The starting compound (XIII) used in the above-mentioned reaction (h)can be produced by a method known per se, for example, the methoddescribed in Journal of Medicinal Chemistry, vol. 37, p. 2371 (1994) ora method analogous thereto, or the production methods shown in theaforementioned reactions (d) to (g) or methods analogous thereto.

The above-mentioned reaction (h) may be also promoted by a method knownper se, for example, the method described in Journal of the AmericanChemical Society, vol. 124, p. 7421 (2002) and the like or a methodanalogous thereto, in the presence of a metal catalyst.

Examples of the metal catalyst include palladium compounds (e.g.,palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and the like),copper compounds (e.g., copper powder, copper(I) chloride, copper(I)iodide, copper(I) acetate and the like), nickel compounds (e.g.,tetrakis(triphenylphosphine)nickel and the like), rhodium compounds(e.g., tris(triphenylphosphine)rhodium chloride and the like), platinumcompounds and the like.

The amount of the metal catalyst to be used is about 0.000001 to 5 molarequivalents, preferably 0.0001 to 1 molar equivalent, relative tocompound (XIII).

The above-mentioned reaction may be performed using a base and a ligand.

Examples of the base include metal alkoxides such as potassiumphenoxide, sodium tert-butoxide and the like; inorganic salts such aspotassium carbonate, sodium carbonate, cesium carbonate, potassiumphosphate etc. and the like.

The amount of the base to be used is about 0.1 to 10 molar equivalents,preferably about 1 to 3 molar equivalents, relative to compound (XIII).

Examples of the ligand include organic phosphorus compounds such astriphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine,BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and the like;organic amine compounds such as N,N′-dimethyl-cyclohexane-1,2-diamine,2,2′-bipyridyl etc. and the like.

The amount of the ligand to be used is about 0.000001 to 5 molarequivalents, preferably about 0.0001 to 1 molar equivalent, relative tocompound (XIII).

When a metal catalyst unstable to oxygen is used in the above-mentionedreaction, the reaction is preferably performed under an inert gas (e.g.,argon, nitrogen and the like) atmosphere.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 120° C.

The reaction time is generally about 0.5 to about 20 hr.

wherein X, X₂, X₃, Y, R1, R6, R90 and R91 are as defined above.

In the above-mentioned reaction (i), compound (XV) is reacted withcompound (XVI) to give compound (Id).

The above-mentioned reaction (i) can be performed by a method similar tothe method shown in reaction (h).

The starting compound (XV) used in the above-mentioned reaction (i) canbe produced by a method known per se, for example, the method describedin Journal of Medicinal Chemistry, vol. 37, p. 2371 (1994) or a methodanalogous thereto, or the production methods shown in the aforementionedreactions (d) to (g) or methods analogous thereto.

wherein X, X₂, X₃, Y, R1, R90 and R91 are as defined above.

In the above-mentioned reaction (j), compound (XV) is reacted withcompound (XVII) to give compound (IIe).

The above-mentioned reaction (j) can be performed by a method similar tothe method shown in reaction (h).

wherein X, X₂, X₃, Y and R1 are as defined above, E4 is a leaving group(e.g., a halogen atom such as chlorine, bromine, iodine etc. and thelike; a substituted sulfonic acid ester such as trifluoromethanesulfonicacid ester etc. and the like), and M is a metal (e.g., potassium,sodium, lithium, magnesium, copper, mercury, zinc, thallium, boron, tin,silicon and the like).

In the above-mentioned reaction (k), compound (XVIII) is reacted withcompound (XIX) to give compound (IIe). The amount of compound (XIX) tobe used is preferably about 1 to about 5 molar equivalents relative tocompound (XVIII).

In the above-mentioned reaction (k), the reaction to obtain compound(IIe) from compound (XVIII) is performed in a solvent that does notadversely influence the reaction.

Preferable examples of such solvent include alcohols (e.g., methanol,ethanol, ethylene glycol and the like), ethers (e.g., diethyl ether,tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane and the like), amides(e.g., N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidoneand the like), aromatic hydrocarbons (e.g., toluene, xylene and thelike) and the like. These solvents may be used as a mixture of two ormore kinds thereof at an appropriate ratio. Furthermore, water may bemixed with the above-mentioned solvent at an appropriate ratio.

In the above-mentioned reaction (k), the reaction to obtain compound(IIe) from compound (XVIII) can be also promoted by a method known perse, for example, the method described in Tetrahedron Letters, vol. 40,p. 8193 (1999) and the like or a method analogous thereto, in thepresence of a metal catalyst.

Examples of the metal catalyst include palladium compounds (e.g.,palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and the like),copper compounds (e.g., copper powder, copper(I) chloride, copper(I)iodide, copper(I) acetate and the like), nickel compounds (e.g.,tetrakis(triphenylphosphine)nickel and the like), rhodium compounds(e.g., tris(triphenylphosphine)rhodium chloride and the like), platinumcompounds and the like.

The amount of the metal catalyst to be used is about 0.000001 to 5 molarequivalents, preferably 0.0001 to 1 molar equivalent, relative tocompound (XVIII).

The above-mentioned reaction may be performed using a ligand. Examplesof the ligand include organic phosphorus compounds such astriphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine,BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and the like;organic amine compounds such as N,N′-dimethyl-cyclohexane-1,2-diamine,2,2′-bipyridyl etc. and the like.

The amount of the ligand to be used is about 0.000001 to 5 molarequivalents, preferably about 0.00001 to 1 molar equivalent, relative tocompound (XVIII).

When a metal catalyst unstable to oxygen is used, this reaction ispreferably performed under an inert gas (e.g., argon, nitrogen and thelike) atmosphere.

The reaction temperature is generally about −50° C. to about 300° C.,preferably about −10° C. to about 150° C.

The reaction time is generally about 0.5 to about 20 hr.

The starting compound (XVIII) used in the above-mentioned reaction (k)can be produced by a method known per se, for example, the methoddescribed in Journal of Medicinal Chemistry, vol. 37, p. 2371 (1994) ora method analogous thereto, or the production methods shown in theaforementioned reactions (d) to (g) or methods analogous thereto.

wherein X, X₃, Y and R1 are as defined above, R101 is a C6-C14 arylgroup or a aromatic heterocyclic group, and R100 is a C1-C6 alkyl groupor a C3-C10 cycloalkyl group (these groups may be optionally substitutedby 1 to 3 substituents selected from a halogen, a hydroxy group and thelike, respectively). E5 and E6 are both leaving groups (e.g., a halogenatom such as chlorine, bromine, iodine and the like; a substitutedsulfonic acid ester such as methanesulfonic acid ester,p-toluenesulfonic acid ester and the like), and/or a hydroxy group.

In the above-mentioned reaction (1), compound (XX) is reacted withcompound (XXI) to give compound (IIf).

The reaction to obtain compound (IIf) is performed using about 1 to 10mol of compound (XXI) per 1 mol of compound (XX), in an organic solventthat does not adversely influence the reaction.

The starting compound (XX) used in the above-mentioned reaction (1) canbe produced by a method known per se, for example, the method describedin Journal of Medicinal Chemistry, vol. 37, p. 2371 (1994) or a methodanalogous thereto, or the production methods shown in the aforementionedreactions (d) to (g) or methods analogous thereto.

In the above-mentioned reaction (1), when E5 is a leaving group (e.g., ahalogen atom such as chlorine, bromine, iodine and the like; asubstituted sulfonic acid ester such as trifluoromethanesulfonic acidester etc. and the like), and E6 is a hydroxy group, the reaction can bealso promoted by a method known per se, for example, the methoddescribed in Journal of the American Chemical Society, vol. 127, p. 8146(2005) and the like or a method analogous thereto, in the presence of ametal catalyst.

Examples of the metal catalyst include palladium compounds (e.g.,palladium acetate, palladium chloride,tetrakis(triphenylphosphine)palladium,dichlorobis(triphenylphosphine)palladium,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium and the like),copper compounds (e.g., copper powder, copper(I) chloride, copper(I)iodide, copper(I) acetate and the like), nickel compounds (e.g.,tetrakis(triphenylphosphine)nickel and the like), rhodium compounds(e.g., tris(triphenylphosphine)rhodium chloride and the like), platinumcompounds and the like.

The amount of the metal catalyst to be used is about 0.000001 to 5 molarequivalents, preferably 0.0001 to 1 molar equivalent, relative tocompound (XX).

The above-mentioned reaction may be performed using a base and a ligand.

Examples of the base include metal alkoxides such as potassiumphenoxide, sodium tert-butoxide and the like; inorganic salts such aspotassium carbonate, sodium carbonate, cesium carbonate, potassiumphosphate and the like, and the like.

The amount of the base to be used is about 0.1 to 10 molar equivalents,preferably about 1 to 3 molar equivalents, relative to compound (XX).

Examples of the ligand include organic phosphorus compounds such astriphenylphosphine, tri-tert-butylphosphine, tricyclohexylphosphine,BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) and the like;organic amine compounds such as N,N′-dimethyl-cyclohexane-1,2-diamine,2,2′-bipyridyl and the like, and the like.

The amount of the ligand to be used is about 0.000001 to 5 molarequivalents, preferably about 0.00001 to 1 molar equivalent, relative tocompound (XX).

Examples of the solvent that does not adversely influence the reactioninclude alcohols such as methanol, ethanol, ethylene glycol and thelike; ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane and thelike; halogenated hydrocarbons such as chloroform, dichloromethane andthe like; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; amides such as N,N-dimethylformamide and the like; sulfoxides suchas dimethyl sulfoxide etc. and the like. These solvents may be used as amixture of two or more kinds thereof at an appropriate ratio.Furthermore, water may be mixed with the above-mentioned solvent at anappropriate ratio.

When a metal catalyst unstable to oxygen is used in the above-mentionedreaction, the reaction is preferably performed under an inert gas (e.g.,argon, nitrogen and the like) atmosphere.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 120° C.

The reaction time is generally about 0.5 to about 20 hr.

In the above-mentioned reaction (1), when E5 and E6 are both hydroxygroups, the reaction is performed by a method known per se, for example,the method described in Organic Reactions, vol. 42, p. 335 (1992) andthe like or a method analogous thereto. This reaction is performed inthe presence of an organic phosphorus compound and an azo reagent.

Examples of the organic phosphorus compound include triphenylphosphine,tri(n-butyl)phosphine and the like.

Examples of the azo reagent include diethyl azodicarboxylate,diisopropyl azodicarboxylate, 1,1′-(azodicarbonyl)dipiperidine and thelike.

The amount of the organic phosphorus compound and azo reagent to be usedis preferably about 1 to about 5 molar equivalents relative to compound(XX), respectively.

Examples of the solvent that does not adversely influence the reactioninclude ethers such as diethyl ether, tetrahydrofuran, 1,4-dioxane andthe like; halogenated hydrocarbons such as chloroform, dichloromethaneand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethyl sulfoxide etc. and the like. These solvents may be usedas a mixture of two or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 20 hr.

In the above-mentioned reaction (1), when E5 is a hydroxy group and E6is a leaving group (e.g., a halogen atom such as chlorine, bromine,iodine and the like; a substituted sulfonic acid ester such astrifluoromethanesulfonic acid ester etc. and the like), this reaction isperformed according to a conventional method, in a solvent that does notadversely influence the reaction, in the presence of a base.

Examples of the base include alkali metal salts such as potassiumhydroxide, sodium hydroxide, sodium hydrogen carbonate, potassiumcarbonate and the like; amines such as pyridine, triethylamine,N,N-dimethylaniline, 1,8-diazabicyclo[5.4.0]undec-7-ene and the like;metal hydrides such as potassium hydride, sodium hydride and the like;alkali metal alkoxides such as sodium methoxide, sodium ethoxide,potassium tert-butoxide etc. and the like.

The amount of the base to be used is preferably about 1 to about 5 molarequivalents relative to compound (XX).

Examples of the solvent that does not adversely influence the reactioninclude aromatic hydrocarbons such as benzene, toluene, xylene and thelike; nitrites such as acetonitrile, propionitrile and the like; etherssuch as tetrahydrofuran, 1,4-dioxane, diethyl ether and the like;ketones such as acetone, 2-butanone and the like; halogenatedhydrocarbons such as chloroform, dichloromethane and the like; amidessuch as N,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxide etc. and the like. These solvents may be used as a mixture oftwo or more kinds thereof at an appropriate ratio.

The reaction temperature is generally about −50° C. to about 150° C.,preferably about −10° C. to about 100° C.

The reaction time is generally about 0.5 to about 20 hr.

The starting compound (XX) used in the above-mentioned reaction (1) canbe produced by a method known per se, for example, the method describedin Journal of Medicinal Chemistry, vol. 37, p. 2371 (1994) or a methodanalogous thereto, or the production methods shown in the aforementionedreactions (d) to (g) and (j) to (k) or methods analogous thereto.

In each of the aforementioned reactions, when the starting compound hasa hydroxy group, an amino group, a carboxyl group or a carbonyl group asa substituent, a protecting group generally used in the peptidechemistry and the like may be introduced into these groups. By removingthe protecting group as necessary after the reaction, the objectcompound can be obtained.

Examples of the protecting group of hydroxy group include C1-C6 alkylgroup (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl),phenyl group, trityl group, C7-C10 aralkyl group (e.g., benzyl), formylgroup, C1-C6 alkyl-carbonyl group (e.g., acetyl, propionyl), benzoylgroup, C7-C10 aralkyl-carbonyl group (e.g., benzylcarbonyl),2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, silyl group (e.g.,trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl), C2-C6 alkenyl group(e.g., 1-allyl) and the like. These groups are optionally substituted by1 to 3 substituents selected from halogen atom (e.g., fluorine,chlorine, bromine, iodine), C1-C6 alkyl group (e.g., methyl, ethyl,propyl), C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy), nitrogroup and the like.

Examples of the amino-protecting group include formyl group, C1-C6alkyl-carbonyl group (e.g., acetyl, propionyl), C1-C6 alkoxy-carbonylgroup (e.g., methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl),benzoyl group, C7-C10 aralkyl-carbonyl group (e.g., benzylcarbonyl),C7-C14 aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl,9-fluorenylmethoxycarbonyl), trityl group, phthaloyl group,N,N-dimethylaminomethylene group, silyl group (e.g., trimethylsilyl,triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl,tert-butyldiethylsilyl), C2-C6 alkenyl group (e.g., 1-allyl) and thelike. These groups are optionally substituted by 1 to 3 substituentsselected from halogen atom (e.g., fluorine, chlorine, bromine, iodine),C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy), nitro group and thelike.

Examples of the protecting group of carboxyl group include C1-C6 alkylgroup (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl),C7-C10 aralkyl group (e.g., benzyl), phenyl group, trityl group, silylgroup (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl,tert-butyldimethylsilyl, tert-butyldiethylsilyl,tert-butyldiphenylsilyl), C2-C6 alkenyl group (e.g., 1-allyl) and thelike. These groups are optionally substituted by 1 to 3 substituentsselected from halogen atom (e.g., fluorine, chlorine, bromine, iodine),C1-C6 alkoxy group (e.g., methoxy, ethoxy, propoxy), nitro group and thelike.

Examples of the protecting group of carbonyl group include cyclic acetal(e.g., 1,3-dioxane), acyclic acetal (e.g., di-C1-C6 alkyl acetal) andthe like.

These protecting groups can be removed according to a method known perse, for example, the method described in Protective Groups in OrganicSynthesis, John Wiley and Sons (1980) and the like. For example, amethod using acid, base, ultraviolet rays, hydrazine, phenylhydrazine,sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladiumacetate, trialkylsilyl halide (e.g., trimethylsilyl iodide,trimethylsilyl bromide and the like) and the like, reduction method andthe like can be used.

When compound (I) contains an optical isomer, a stereoisomer, aregioisomer or a rotamer, these are also encompassed in compound (I),and can be obtained as a single product according to synthesis andseparation methods known per se. For example, when compound (I) has anoptical isomer, an optical isomer resolved from this compound is alsoencompassed in compound (I).

The optical isomer can be produced by a method known per se. To bespecific, an optically active synthetic intermediate is used, or thefinal racemate product is subjected to optical resolution according to aconventional method to give an optical isomer.

The method of optical resolution may be a method known per se, such as afractional recrystallization method, a chiral column method, adiastereomer method, etc.

1) Fractional Recrystallization Method

A method wherein a salt of a racemate with an optically active compound(e.g., (+)-mandelic acid, (−)-mandelic acid, (+)-tartaric acid,(−)-tartaric acid, (+)-1-phenethylamine, (−)-1-phenethylamine,(+)-cinchonine, (−)-cinchonidine, brucine, etc.) is formed, which isseparated by a fractional recrystallization method, and if desired, afree optical isomer is obtained by a neutralization step.

2) Chiral Column Method

A method wherein a racemate or a salt thereof is applied to a column forseparation of an optical isomer (a chiral column) to allow separation.In the case of a liquid chromatography, for example, a mixture of theoptical isomers is applied to a chiral column such as ENANTIO-OVM(manufactured by Tosoh Corporation), CHIRAL series (manufactured byDaicel Chemical Industries, Ltd.) and the like, and developed withwater, various buffers (phosphate buffer, etc.) and organic solvents(ethanol, methanol, isopropanol, acetonitrile, trifluoroacetic acid,diethylamine, etc.) solely or in admixture to separate the opticalisomer.

3) Diastereomer Method

A method wherein a racemic mixture is prepared into a diastereomericmixture by chemical reaction with an optically active reagent, which ismade into a single substance by a typical separation means (a fractionalrecrystallization method, a chromatography method, etc.) and the like,and is subjected to a chemical treatment such as hydrolysis and the liketo separate an optically active reagent moiety, whereby an opticalisomer is obtained. For example, when compound (I) contains hydroxy, orprimary or secondary amino in a molecule, the compound and an opticallyactive organic acid (MTPA [α-methoxy-α-(trifluoromethyl)phenylaceticacid], (−)-menthoxyacetic acid, etc.) and the like are subjected tocondensation reaction to give diastereomers in the ester form or in theamide form, respectively. When compound (I) has a carboxylic acid group,this compound and an optically active amine or an alcohol reagent aresubjected to condensation reaction to give diastereomers in the amideform or in the ester form, respectively. The separated diastereomer isconverted to an optical isomer of the original compound by acidhydrolysis or base hydrolysis.

EXAMPLES

The present invention is described in detail by way of the followingExperimental Examples, Reference Examples, Examples and FormulationExamples, which are not to be construed as limitative.

In the following Reference Examples and Examples, the room temperaturemeans 1° C.-30° C.

As for NMR spectra, the chemical shift was indicated by δ, and acoupling constant was indicated by Hz. The numeric value in parenthesiswith regard to a mixed solvent is a volumetric mixing ratio of eachsolvent. Moreover, “%” in the solution represents the number of grams in100 ml of a solution. The abbreviations used in the presentspecification mean the following.

s: singletd: doublett: tripletq: quartetdd: double doubletdt: double tripletm: multipletbr: broadJ: coupling constantCDCl₃: deuterated chloroformDMSO-d₆: dimethyl sulfoxide-d₆¹H NMR: proton nuclear magnetic resonanceTBS: tert-butyl(dimethyl)silylTBDMS: tert-butyl(dimethyl)silylTIPS: triisopropylsilyl

As for X-ray analysis, the X-ray powder diffraction pattern of thiscrystal was measured using Cu—Kα ray (tube voltage: 40 KV; tube current:50 mA) as a radiation source with scan speed of 6.000°/min.

Example 13-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

1a)4′-[(2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A solution of methyl imidocarbamate sulfate (10 g), 28% sodium methoxide(26 mL) and ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (15.8g) in methanol (100 mL) was stirred overnight at room temperature. Thesolvent was evaporated under reduced pressure, and water and acetic acidwere added. The precipitated solid was collected by filtration, washedwith water and diethyl ether to give the title compound (2.62 g, 16%) asa colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.46-1.64 (2H, m), 2.46(2H, t, J=7.2), 3.82 (2H, s), 3.86 (3H, s), 7.32 (2H, d, J=8.4), 7.47(2H, d, J=8.4), 7.52-7.63 (2H, m), 7.72-7.82 (1H, m), 7.92 (1H, d,J=6.6), 12.21 (1H, br)

1b)4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.6 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (2.78g), triethylamine (5.0 mL), pyridine (2.9 mL) and molecular sieves 4 A(5.2 g) in dichloromethane (50 mL) was added copper(II) acetate (2.6 g),and the mixture was stirred for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (1.85 g, 51%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.2), 1.44 (6H, s), 1.55-1.70(2H, m), 2.54 (2H, t, J=7.2), 3.04 (2H, s), 3.82 (3H, s), 3.83 (2H, s),6.75 (1H, d, J=8.4), 6.99 (1H, d, J=8.4), 7.09 (1H, s), 7.37 (2H, d,J=8.4), 7.48 (2H, d, J=8.4), 7.52-7.62 (2H, m), 7.73-7.81 (1H, m), 7.93(1H, d, J=7.8)

1c)3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (4.33 g), sodium hydrogencarbonate (6.16 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min,4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.85 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate, and the solvent was evaporated. The residue was dissolved intetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.48 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.74 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.44 (6H, s), 1.50-1.67(2H, m), 2.50-2.60 (2H, m), 3.04 (2H, s), 3.81 (3H, s), 3.83 (2H, s),6.75 (1H, d, J=8.4), 6.97 (1H, d, J=8.4), 7.08 (1H, s), 7.17-7.32 (4H,m), 7.46-7.58 (2H, m), 7.61-7.73 (2H, m), 12.37 (1H, s)

Example 22-(dimethylamino)-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

2a)4′-{[2-(dimethylamino)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate(6.41 g) and N,N-dimethylguanidine sulfate (5.0 g) in ethanol (100 mL)was added 20% sodium ethoxide-ethanol solution (11 mL), and the mixturewas heated under reflux for 24 hr. The reaction mixture was allowed tocool to room temperature, and the solvent was evaporated under reducedpressure. The residue was washed with water and diethyl ether to givethe title compound (2.06 g, 30%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.5), 1.42-1.63 (2H, m), 2.37(2H, t, J=7.5), 3.02 (6H, s), 3.78 (2H, s), 7.31 (2H, d, J=7.8), 7.46(2H, d, J=7.8), 7.50-7.63 (2H, m), 7.70-7.82 (1H, m), 7.92 (1H, d,J=8.1), 10.94 (1H, br)

2b)4′-{[2-(dimethylamino)-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-{[2-(dimethylamino)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.1 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (2.1g), triethylamine (3.8 mL), pyridine (2.2 mL) and molecular sieves 4 A(4 g) in dichloromethane (50 mL) was added copper(II) acetate (2 g), andthe mixture was stirred for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.31 g, 11%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (3H, t, J=7.2), 1.47 (6H, s), 1.52-1.62(2H, m), 2.17 (2H, s), 2.61 (2H, t, J=7.2), 2.99 (6H, s), 4.04 (2H, s),6.65 (1H, d, J=9.3), 6.78-6.87 (2H, m), 7.30-7.52 (6H, m), 7.57-7.66(1H, m), 7.74 (1H, d, J=7.5)

2c)2-(dimethylamino)-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogencarbonate (1.01 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-(dimethylamino)-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.31 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate, and the solvent was evaporated. The residue was dissolved intetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.13 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.1 g, 33%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.2), 1.40 (6H, s), 1.49-1.65(2H, m), 2.50-2.58 (2H, m), 2.91 (6H, s), 2.99 (2H, s), 3.98 (2H, s),6.66 (1H, d, J=8.7), 6.81 (1H, d, J=8.7), 6.90 (1H, s), 7.25 (4H, s),7.47-7.59 (2H, m), 7.61-7.72 (2H, m), 12.36 (1H, br)

Example 35-benzyl-2-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

3a) 5-benzyl-2-(ethylthio)-6-methylpyrimidin-4(3H)-one

To a solution of5-benzyl-6-methyl-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (0.2 g) andpotassium carbonate (0.24 g) in N,N-dimethylformamide (4 mL) was addedethyl iodide (0.035 mL), and the mixture was stirred for 4 hr. Theinsoluble material was filtered off. The filtrate was diluted with ethylacetate, washed with 1 M hydrochloric acid and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure to give the title compound (0.22 g, 97%) as apale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (3H, t, J=7.5), 2.18 (3H, s), 3.08 (2H,q, J=7.5), 3.74 (2H, s), 7.02-7.34 (5H, m)

3b)5-benzyl-2-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of 5-benzyl-2-(ethylthio)-6-methylpyrimidin-4(3H)-one(0.22 g) and3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole(0.44 g) in N,N-dimethylformamide (5 mL) was added cesium carbonate(0.36 g), and the mixture was stirred for 12 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran-ethanol (1:1, 4 mL), 1 M sodium hydroxide (2 mL) wasadded and the mixture was stirred for 30 min. The reaction mixture wasweakly acidified with 1 M hydrochloric acid and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound (0.025 g, 6%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.35 (3H, t, J=7.5), 2.27 (3H, s), 3.17 (2H,q, J=7.5), 3.76 (2H, s), 5.20 (2H, s), 7.07-7.30 (9H, m), 7.37-7.47 (2H,m), 7.52-7.62 (1H, m), 7.66 (1H, d, J=7.5)

5-Benzyl-2-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   5-benzyl-2-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   5-benzyl-2-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   5-benzyl-2-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   5-benzyl-2-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   5-benzyl-2-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 45-benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

4a) 5-benzyl-2-ethoxy-6-methylpyrimidin-4(3H)-one

To a solution of ethyl imidocarbamate tetrafluoroborate (2.4 g) andethyl 2-benzyl-3-oxobutanoate (1 g) in methanol (20 mL) was added sodiummethoxide (28% methanol solution, 5.25 mL), and the mixture was stirredfor 12 hr. The reaction mixture was concentrated, and the residue wasdissolved in water. The solution was weakly acidified with acetic acid,extracted with ethyl acetate, washed with saturated brine and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was crystallized from diisopropyl ether to givethe title compound (0.27 g, 24%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (3H, t, J=7.2), 2.12 (3H, s), 3.70 (2H,s), 4.31 (2H, q, J=7.2), 7.03-7.33 (5H, m), 12.17 (1H, br)

4b)5-benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of 5-benzyl-2-ethoxy-6-methylpyrimidin-4(3H)-one (0.27 g)and3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole(0.58 g) in N,N-dimethylformamide (5 mL) was added cesium carbonate(0.44 g), and the mixture was stirred for 12 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran-ethanol (1:1, 4 mL), 1 M sodium hydroxide (2 mL) wasadded and the mixture was stirred for 30 min. The reaction mixture wasweakly acidified with 1 M hydrochloric acid and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound (0.11 g, 20%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7.2), 2.20 (3H, s), 3.78 (2H,s), 4.43 (2H, q, J=7.2), 5.14 (2H, s), 7.10-7.30 (7H, m), 7.34-7.51 (4H,m), 7.55-7.64 (1H, m), 7.75 (1H, d, J=7.8)

5-Benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   5-benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   5-benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   5-benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   5-benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   5-benzyl-2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 52-butyl-5-(4-fluorophenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

5a)4′-[(2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of 2-butyl-6-methylpyrimidin-4(3H)-one (3.38 g) and4′-(bromomethyl)biphenyl-2-carbonitrile (6.64 g) in acetonitrile (50 mL)was added cesium carbonate (8.61 g), and the mixture was stirred at 50°C. for 12 hr. The insoluble material was filtered off, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound (2.09 g, 29%) as a colorlessviscous substance.

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.2), 1.30-1.46 (2H, m),1.61-1.74 (2H, m), 2.29 (3H, s), 2.68 (2H, t, J=6.6), 5.36 (2H, s), 6.29(1H, s), 7.23-7.32 (2H, m), 7.40-7.57 (4H, m), 7.59-7.69 (1H, m), 7.76(1H, d, J=7.8)

5b)4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.8 g) in acetic acid (40 mL) was added bromine (0.77 mL), and themixture was stirred at 70° C. for 2 hr. The reaction mixture was allowedto cool to room temperature. The mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound (1.96 g, 88%) as acolorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.5), 1.30-1.47 (2H, m),1.60-1.75 (2H, m), 2.49 (3H, s), 2.69 (2H, t, J=7.5), 5.39 (2H, s), 7.31(2H, d, J=8.1), 7.40-7.58 (4H, m), 7.60-7.70 (1H, m), 7.76 (1H, d,J=6.9)

5c)4′-{[2-butyl-5-(4-fluorophenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.0 g) and 4-fluorophenylboronic acid (0.48 g) in 1,4-dioxane (20 mL)were added 2 M aqueous cesium carbonate solution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and themixture was stirred at 90° C. for 12 hr under an argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (1.0 g, 97%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2), 1.34-1.52 (2H, m),1.66-1.81 (2H, m), 2.22 (3H, s), 2.75 (2H, t, J=7.8), 5.38 (2H, s),7.09-7.17 (2H, m), 7.28-7.38 (4H, m), 7.40-7.58 (4H, m), 7.59-7.69 (1H,m), 7.76 (1H, d, J=7.8)

5d)2-butyl-5-(4-fluorophenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.62 g), sodium hydrogencarbonate (3.72 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-5-(4-fluorophenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(1 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (20mL), N,N′-carbonyldiimidazole (0.54 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.81 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.2), 1.21-1.38 (2H, m),1.50-1.66 (2H, m), 2.11 (3H, s), 2.69 (2H, t, J=7.5), 5.36 (2H, s),7.18-7.42 (8H, m), 7.47-7.62 (2H, m), 7.62-7.74 (2H, m), 12.41 (1H, s)

Example 62-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

6a)4′-{[2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.96 g) and 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.54 g) in1,4-dioxane were added 2 M aqueous cesium carbonate solution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.09 g), andthe mixture was stirred at 90° C. for 12 hr under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.75 g, 72%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2), 1.33-1.51 (2H, m),1.65-1.81 (2H, m), 2.24 (3H, s), 2.74 (2H, t, J=7.8), 3.24 (2H, t,J=8.4), 4.59 (2H, t, J=8.4), 5.38 (2H, s), 6.83 (1H, d, J=8.1), 7.05(1H, d, J=8.1), 7.19 (1H, s), 7.34 (2H, d, J=8.1), 7.40-7.57 (4H, m),7.59-7.69 (1H, m), 7.76 (1H, d, J=7.8)

6b)2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.86 g), sodium hydrogencarbonate (2.65 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.75 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (15mL), N,N′-carbonyldiimidazole (0.38 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.63 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.2), 1.21-1.38 (2H, m),1.51-1.65 (2H, m), 2.12 (3H, s), 2.68 (2H, t, J=7.2), 3.20 (2H, t,J=8.4), 4.55 (2H, t, J=8.4), 5.35 (2H, s), 6.78 (1H, d, J=8.1), 7.00(1H, d, J=8.1), 7.16 (1H, s), 7.25 (2H, d, J=8.1), 7.32 (2H, d, J=8.1),7.48-7.61 (2H, m), 7.64-7.74 (2H, m), 12.41 (1H, s)

Example 76-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one

7a)6-methyl-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one

To a solution of ethyl 3-oxo-2-(tetrahydro-2H-pyran-2-ylmethyl)butyrate(0.73 g) and butylamidine hydrochloride (0.78 g) in methanol (50 mL) wasadded sodium methoxide (25 mL, 28% methanol solution), and the mixturewas stirred for 12 hr. The reaction mixture was concentrated, and theresidue was dissolved in water and diethyl ether. The aqueous layer wasseparated, weakly acidified with 1 M hydrochloric acid, and the mixturewas extracted with ethyl acetate. The extract was washed with saturatedbrine, and dried over anhydrous sodium sulfate to give the titlecompound (0.46 g, 57%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.88 (3H, t, J=7.2), 1.08-1.80 (8H, m), 2.18(3H, s), 2.41 (2H, t, J=7.2), 2.48-2.50 (2H, m), 3.12-3.28 (1H, m),3.33-3.47 (1H, m), 3.79 (1H, d, J=10.8), 12.15 (1H, br)

7b)6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one

To a solution of6-methyl-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one(0.46 g) and3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole(0.95 g) in acetonitrile (20 mL) was added potassium carbonate (0.51 g),and the mixture was stirred for 12 hr. The reaction mixture was dilutedwith ethyl acetate, washed with 1 M hydrochloric acid and saturatedbrine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran-ethanol (1:1, 4 mL), 1 M sodium hydroxide (2 mL) wasadded and the mixture was stirred for 30 min. The reaction mixture wasweakly acidified with 1 M hydrochloric acid and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound (0.15 g, 17%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.2), 1.15-1.32 (1H, m),1.32-1.49 (3H, m), 1.49-1.64 (3H, m), 1.75 (1H, m), 2.25 (3H, s),2.54-2.66 (4H, m), 3.16-3.29 (1H, m), 3.37-3.51 (1H, m), 3.81 (1H, d,J=10.2), 5.31 (2H, s), 7.17 (2H, d, J=8.4), 7.29 (2H, d, J=8.4),7.46-7.62 (2H, m), 7.63-7.75 (2H, m), 12.38 (1H, br)

-   6-Methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    obtained above is subjected to a conventional method of salt    formation to give the following salts.-   6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    sodium salt-   6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    potassium salt-   6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    0.5 calcium salt-   6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    hydrochloride-   6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    hydrobromide

Example 82-butyl-5-cyclohex-1-en-1-yl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

8a)4′-[(2-butyl-5-cyclohex-1-en-1-yl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.67 g) and2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.48 g) intetrahydrofuran (40 mL) were added 2 M aqueous cesium carbonate solution(4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.06g), and the mixture was stirred at 70° C. for 12 hr under an argonatmosphere. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off through celite. The filtrate waswashed successively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.58 g, 86%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.5), 1.31-1.46 (2H, m),1.61-1.83 (6H, m), 2.11-2.24 (4H, m), 2.28 (3H, s), 2.67 (2H, t, J=7.8),5.33 (2H, s), 5.63 (1H, s), 7.27-7.34 (2H, m), 7.39-7.57 (4H, m),7.58-7.69 (1H, m), 7.75 (1H, d, J=7.8)

8b)2-butyl-5-cyclohex-1-en-1-yl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.78 g), sodium hydrogencarbonate (1.11 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(2-butyl-5-cyclohex-1-en-1-yl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (15mL), N,N′-carbonyldiimidazole (0.33 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.33 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (3H, t, J=7.5), 1.18-1.35 (2H, m),1.47-1.73 (6H, m), 2.11 (4H, br), 2.18 (3H, s), 2.62 (2H, t, J=7.5),5.29 (2H, s), 5.53 (1H, s), 7.20 (2H, d, J=8.4), 7.30 (2H, d, J=8.4),7.47-7.61 (2H, m), 7.63-7.74 (2H, m), 12.41 (1H, br)

Example 96-ethyl-5-(4-fluorophenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

9a)4′-[(4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of 6-ethyl-2-propylpyrimidin-4(3H)-one (5.0 g) and4′-(bromomethyl)biphenyl-2-carbonitrile (9.0 g) in acetonitrile (150 mL)was added potassium carbonate (8.32 g), and the mixture was stirred at50° C. for 12 hr. The insoluble material was filtered off, the filtratewas concentrated, and the residue was purified by silica gel columnchromatography to give the title compound (4.95 g, 46%) as a colorlessviscous substance.

¹H NMR (300 MHz, CDCl₃) δ 0.98 (3H, t, J=7.5), 1.25 (3H, t, J=7.2),1.67-1.83 (2H, m), 2.56 (2H, q, J=7.2), 2.66 (2H, t, J=7.5), 5.36 (2H,br), 6.29 (1H, s), 7.29 (2H, d, J=8.1), 7.40-7.59 (4H, m), 7.60-7.70(1H, m), 7.76 (1H, d, J=7.8)

9b)4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(4.95 g) and sodium acetate (1.25 g) in acetic acid (100 mL) was addedbromine (0.78 mL), and the mixture was stirred for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueoussodium hydrogen carbonate and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (4.3 g, 71%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.98 (3H, t, J=7.2), 1.26 (3H, t, J=7.2),1.70-1.83 (2H, m), 2.68 (2H, t, J=7.2), 2.79 (2H, q, J=7.2), 5.39 (2H,br), 7.32 (2H, d, J=8.1), 7.42-7.55 (4H, m), 7.62-7.67 (1H, m), 7.76(1H, d, J=7.5)

9c)4′-{[4-ethyl-5-(4-fluorophenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.0 g) and 4-fluorophenylboronic acid (0.48 g) in 1,4-dioxane (20 mL)were added 2 M aqueous cesium carbonate solution (4 mL) and[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (0.1 g), andthe mixture was stirred at 90° C. for 12 hr under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.94 g, 91%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.2), 1.18 (3H, t, J=7.5),1.73-1.90 (2H, m), 2.45 (2H, q, J=7.5), 2.74 (2H, t, J=7.2), 5.37 (2H,s), 7.04-7.16 (2H, m), 7.24-7.39 (4H, m), 7.40-7.57 (4H, m), 7.60-7.69(1H, m), 7.76 (1H, d, J=8.1)

9d)6-ethyl-5-(4-fluorophenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.46 g), sodium hydrogencarbonate (3.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(4-fluorophenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.94 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (15mL), N,N′-carbonyldiimidazole (0.51 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.77 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.5), 1.10 (3H, t, J=7.2),1.57-1.75 (2H, m), 2.34 (2H, q, J=7.2), 2.69 (2H, t, J=7.5), 5.35 (2H,s), 7.18-7.40 (8H, m), 7.48-7.62 (2H, m), 7.62-7.76 (2H, m), 12.40 (1H,br)

Example 105-(2,3-dihydro-1-benzofuran-5-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

10a)4′-{[5-(2,3-dihydro-1-benzofuran-5-yl)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.0 g) and 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.56 g) in1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.09g), and the mixture was stirred at 90° C. for 12 hr under an argonatmosphere. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off through celite. The filtrate waswashed successively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.95 g, 87%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.2), 1.18 (3H, t, J=7.2),1.71-1.91 (2H, m), 2.49 (2H, q, J=7.2), 2.73 (2H, t, J=8.1), 3.24 (2H,t, J=8.4), 4.58 (2H, t, J=8.4), 5.37 (2H, s), 6.83 (1H, d, J=8.4),6.98-7.06 (1H, m), 7.16 (1H, br), 7.35 (2H, d, J=8.1), 7.41-7.57 (4H,m), 7.60-7.68 (1H, m), 7.76 (1H, d, J=6.9)

10b)5-(2,3-dihydro-1-benzofuran-5-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.36 g), sodium hydrogencarbonate (3.36 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-(2,3-dihydro-1-benzofuran-5-yl)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.95 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (15mL), N,N′-carbonyldiimidazole (0.49 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.46 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.69 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.5), 1.10 (3H, t, J=7.5),1.58-1.73 (2H, m), 2.36 (2H, q, J=7.5), 2.68 (2H, t, J=7.5), 3.20 (2H,t, J=8.1), 4.55 (2H, t, J=8.1), 5.33 (2H, s), 6.79 (1H, d, J=8.1), 6.98(1H, d, J=8.1), 7.12 (1H, s), 7.21-7.35 (4H, m), 7.46-7.61 (2H, m),7.62-7.76 (2H, m), 12.40 (1H, s)

Example 115-cyclopropyl-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

11a)4′-[(5-cyclopropyl-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.0 g), cyclopropylboronic acid (0.26 g), potassium phosphate (1.7 g)and tricyclohexylphosphine (0.064 g) in toluene-water (20:1, 21 mL) wasadded palladium acetate (0.026 g), and the mixture was stirred at 100°C. for 12 hr under an argon atmosphere. The reaction mixture was dilutedwith ethyl acetate, and the insoluble material was filtered off throughcelite. The filtrate was washed successively with 1 M hydrochloric acid,saturated aqueous sodium hydrogen carbonate and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.79 g, 87%) as a colorlesssolid.

¹H NMR (300 MHz, CDCl₃) δ 0.77-0.86 (2H, m), 0.89-1.04 (5H, m), 1.26(3H, t, J=7.2), 1.50-1.60 (1H, m), 1.65-1.82 (2H, m), 2.64 (2H, q,J=7.2), 2.79 (2H, t, J=7.2), 5.30 (2H, s), 7.27-7.37 (2H, m), 7.39-7.57(4H, m), 7.59-7.69 (1H, m), 7.76 (1H, d, J=7.8)

11b)5-cyclopropyl-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.35 g), sodium hydrogencarbonate (3.34 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(5-cyclopropyl-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.79 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (15mL), N,N′-carbonyldiimidazole (0.48 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.38 g, 42%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.77-0.91 (7H, m), 1.18 (3H, t, J=7.2),1.51-1.66 (3H, m), 2.55 (2H, t, J=7.2), 2.69 (2H, q, J=7.5), 5.26 (2H,s), 7.17 (2H, d, J=7.8), 7.29 (2H, d, J=7.8), 7.49-7.60 (2H, m),7.63-7.74 (2H, m), 12.39 (1H, br)

Example 122-butyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-fluorophenyl)-6-methylpyrimidin-4(3H)-one

12a)4′-[(2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile

To a solution of 2-butyl-6-methylpyrimidin-4(3H)-one (2.24 g) and4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (4.3 g) inacetonitrile (30 mL) was added potassium carbonate (3.72 g), and themixture was stirred at 50° C. for 12 hr. The insoluble material wasfiltered off, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compound(1.48 g, 29%) as a colorless viscous substance.

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.2), 1.31-1.47 (2H, m),1.63-1.76 (2H, m), 2.29 (3H, s), 2.68 (2H, t, J=7.2), 5.39 (2H, s), 6.29(1H, s), 7.08-7.19 (1H, m), 7.24-7.35 (2H, m), 7.42-7.52 (2H, m),7.60-7.71 (1H, m), 7.77 (1H, d, J=8.1)

12b)4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile

To a solution of4′-[(2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(1.48 g) and sodium acetate (0.36 g) in acetic acid (20 mL) was addedbromine (0.22 mL), and the mixture was stirred for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueoussodium hydrogen carbonate and saturated brine and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (1.07 g, 60%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.92 (3H, t, J=7.2), 1.32-1.48 (2H, m),1.63-1.76 (2H, m), 2.50 (3H, s), 2.69 (2H, t, J=7.2), 5.42 (2H, s),7.15-7.36 (3H, m), 7.48 (2H, t, J=7.5), 7.60-7.71 (1H, m), 7.77 (1H, d,J=8.1)

12c)4′-{[2-butyl-5-(4-fluorophenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.5 g) and 4-fluorophenylboronic acid (0.23 g) in 1,4-dioxane (10 mL)were added 2 M aqueous cesium carbonate solution (2 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), andthe mixture was stirred at 90° C. for 12 hr under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.51 g, 98%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.2), 1.37-1.51 (2H, m),1.67-1.81 (2H, m), 2.23 (3H, s), 2.74 (2H, t, J=7.8), 5.41 (2H, s),7.06-7.16 (2H, m), 7.21-7.36 (5H, m), 7.43-7.53 (2H, m), 7.61-7.71 (1H,m), 7.77 (1H, d, J=6.9)

12d)2-butyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-fluorophenyl)-6-methylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.02 g), sodium hydrogencarbonate (1.45 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-5-(4-fluorophenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.51 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (15mL), N,N′-carbonyldiimidazole (0.26 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.41 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.5), 1.24-1.41 (2H, m),1.52-1.70 (2H, m), 2.13 (3H, s), 2.71 (2H, t, J=7.5), 5.36 (2H, s),6.96-7.14 (2H, m), 7.18-7.29 (3H, m), 7.30-7.39 (2H, m), 7.50-7.64 (2H,m), 7.65-7.75 (2H, m), 12.49 (1H, br)

Example 132-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methylpyrimidin-4(3H)-one

13a)4′-{[2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.5 g) and 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.27 g) in1,4-dioxane (10 mL) were added 2 M aqueous cesium carbonate solution (2mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05g), and the mixture was stirred at 90° C. for 12 hr under an argonatmosphere. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off through celite. The filtrate waswashed successively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.43 g, 79%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.2), 1.35-1.51 (2H, m),1.66-1.82 (2H, m), 2.25 (3H, s), 2.73 (2H, t, J=8.1), 3.25 (2H, t,J=8.7), 4.59 (2H, t, J=8.7), 5.41 (2H, s), 6.83 (1H, d, J=8.1), 7.05(1H, d, J=8.4), 7.19 (1H, s), 7.24-7.36 (3H, m), 7.43-7.53 (2H, m),7.61-7.71 (1H, m), 7.77 (1H, d, J=7.2)

13b)2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.02 g), sodium hydrogencarbonate (1.45 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.21 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.38 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.5), 1.24-1.40 (2H, m),1.53-1.70 (2H, m), 2.13 (3H, s), 2.70 (2H, t, J=7.5), 3.19 (2H, t,J=8.7), 4.55 (2H, t, J=8.7), 5.34 (2H, s), 6.78 (1H, d, J=8.4),6.94-7.17 (4H, m), 7.19-7.29 (1H, m), 7.50-7.64 (2H, m), 7.65-7.75 (2H,m), 12.49 (1H, br)

Example 143-(4′-{[3-butyl-1-(2,2-dimethylpropyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

14a)4′-{[3-butyl-1-(2,2-dimethylpropyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.24 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-iodo-2,2-dimethylpropane (2mL) was added, and the mixture was stirred at 40° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.6 g,50%).

¹H NMR (300 MHz, CDCl₃) δ 0.88 (3H, t, J=7.3), 1.01 (9H, s), 1.35 (2H,dq, J=7.5, 7.3), 1.52-1.65 (2H, m), 2.39-2.46 (2H, m), 3.61 (2H, s),4.90 (2H, s), 7.35 (2H, d, J=8.5), 7.42-7.57 (4H, m), 7.65 (1H, dt,J=7.7, 1.3), 7.77 (1H, dd, J=7.6, 0.8)

14b)3-(4′-{[3-butyl-1-(2,2-dimethylpropyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

A mixture of hydroxylammonium chloride (1.24 g), sodium hydrogencarbonate (1.88 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[3-butyl-1-(2,2-dimethylpropyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile(0.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.29 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.46 g,72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (3H, t, J=7.3), 0.93 (9H, s), 1.17-1.33(2H, m), 1.37-1.54 (2H, m), 2.43 (2H, t, J=7.4), 3.48 (2H, s), 4.88 (2H,s), 7.20-7.36 (4H, m), 7.47-7.61 (2H, m), 7.64-7.76 (2H, m), 12.40 (1H,s)

Example 15

6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one

To a solution of6-methyl-2-propyl-5-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one (0.51 g) and3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole(1.0 g) in acetonitrile (20 mL) was added potassium carbonate (0.58 g),and the mixture was stirred for 12 hr. The reaction mixture was dilutedwith ethyl acetate, washed with 1 M hydrochloric acid and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran-ethanol (1:1, 4 mL), 1 M sodium hydroxide (2 mL) wasadded and the mixture was stirred for 30 min. The reaction mixture wasweakly acidified with 1 M hydrochloric acid and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound (0.043 g, 4%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.52-1.67 (2H, m), 2.27(3H, s), 2.62 (2H, t, J=7.2), 4.00 (2H, s), 5.33 (2H, s), 7.15-7.27 (4H,m), 7.30 (2H, d, J=8.1), 7.49-7.61 (2H, m), 7.63-7.75 (3H, s), 8.44 (1H,d, J=3.6), 12.41 (1H, br)

Example 165-(3-acetylbenzyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

16a) ethyl 2-(3-acetylbenzyl)-3-oxobutanoate

A solution of 3-acetylbenzyl bromide (4 g) and ethyl acetoacetate sodiumsalt (3.42 g) in tetrahydrofuran (50 mL) was stirred for 12 hr. Theinsoluble material was filtered off and the filtrate was concentrated.The residue was purified by silica gel column chromatography to give thetitle compound (2.42 g, 49%) as a colorless viscous oil.

¹H NMR (300 MHz, CDCl₃) δ 1.21 (3H, t, J=7.2), 2.20 (3H, s), 2.59 (3H,s), 3.21 (2H, d, J=7.2), 3.80 (1H, d, J=7.2), 4.15 (2H, q, J=7.2),7.31-7.47 (2H, m), 7.74-7.86 (2H, m)

16b) 5-(3-acetylbenzyl)-6-methyl-2-propylpyrimidin-4(3H)-one

To a solution of ethyl 2-(3-acetylbenzyl)-3-oxobutanoate (2.39 g) andbutanimidamide hydrochloride (1.68 g) in methanol (20 mL) was added 28%sodium methoxide-methanol solution (5.27 mL), and the mixture wasstirred for 12 hr. The reaction mixture was concentrated, and theresidue was dissolved in water and diethyl ether. The aqueous layer wasseparated, and weakly acidified with 1 M hydrochloric acid. Theprecipitate was collected by filtration and dried under reduced pressureto give the title compound (2.02 g, 78%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.5), 1.55-1.74 (2H, m), 2.18(3H, s), 2.45 (2H, t, J=7.5), 2.54 (3H, s), 3.83 (2H, s), 7.33-7.52 (2H,m), 7.68-7.86 (2H, m), 12.31 (1H, br)

16c)5-(3-acetylbenzyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

To a solution of 5-(3-acetylbenzyl)-6-methyl-2-propylpyrimidin-4(3H)-one(1 g) and3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole(1.68 g) in acetonitrile (30 mL) was added potassium carbonate (0.98 g),and the mixture was stirred for 12 hr. The reaction mixture was dilutedwith ethyl acetate, washed with 1 M hydrochloric acid and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran-ethanol (1:1, 8 mL), 1 M sodium hydroxide (2 mL) wasadded, and the mixture was stirred for 30 min. The reaction mixture wasweakly acidified with 1 M hydrochloric acid, and extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound (0.40 g, 21%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.2), 1.51-1.66 (2H, m), 2.25(3H, s), 2.54 (3H, s), 2.62 (2H, t, J=7.2), 3.93 (2H, s), 5.36 (2H, s),7.20 (2H, d, J=8.4), 7.31 (2H, d, J=8.4), 7.39-7.61 (4H, m), 7.63-7.74(2H, m), 7.75-7.83 (2H, m), 12.40 (1H, s)

Example 17

5-[3-(1-hydroxyethyl)benzyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

To a solution of5-(3-acetylbenzyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.20 g) in tetrahydrofuran-methanol (1:1, 4 mL) was added sodiumborohydride (0.014 g), and the mixture was stirred for 30 min. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, saturated aqueous sodium hydrogen carbonate andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography to give the title compound (0.14 g,69%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.2), 1.27 (3H, d, J=6.6),1.52-1.65 (2H, m), 2.23 (3H, s), 2.61 (2H, t, J=7.2), 3.85 (2H, s),4.58-4.71 (1H, m), 5.10 (1H, d, J=4.2), 5.36 (2H, s), 7.01-7.25 (6H, m),7.29 (2H, d, J=8.1), 7.48-7.61 (2H, m), 7.63-7.74 (2H, m), 12.40 (1H, s)

Example 182-butyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(2-thienyl)pyrimidin-4(3H)-one

18a)4′-{[2-butyl-4-methyl-6-oxo-5-(2-thienyl)pyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g), tributyl(2-thienyl)tin (0.64 g) and lithium chloride (0.15 g)in N,N-dimethylformamide (10 mL) was addeddichlorobis(triphenylphosphine)palladium (0.04 g), and the mixture wasstirred for 12 hr under an argon atmosphere. The reaction mixture wasallowed to cool to room temperature and diluted with ethyl acetate. A20% aqueous potassium fluoride solution was added, and the mixture wasstirred for 2 hr. The insoluble material was filtered off throughcelite. The organic layer of the filtrate was separated, washed with 1 Mhydrochloric acid, saturated aqueous sodium hydrogen carbonate andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was purified bysilica gel column chromatography to give the title compound (0.38 g,75%) as a colorless viscous oil.

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2), 1.33-1.49 (2H, m),1.67-1.79 (2H, m), 2.45 (3H, s), 2.74 (2H, t, J=8.1), 5.41 (2H, s),7.07-7.14 (1H, m), 7.16-7.22 (1H, m), 7.34 (2H, d, J=8.1), 7.40-7.57(5H, m), 7.60-7.59 (1H, m), 7.75 (1H, d, J=7.5)

18b)2-butyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(2-thienyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-4-methyl-6-oxo-5-(2-thienyl)pyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.38 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature. Water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.21 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.38 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.2), 1.22-1.38 (2H, m),1.51-1.66 (2H, m), 2.38 (3H, s), 2.71 (2H, t, J=7.2), 5.38 (2H, s),7.09-7.16 (1H, m), 7.20-7.28 (3H, m), 7.31 (2H, d, J=8.4), 7.48-7.74(5H, m), 12.42 (1H, br)

Example 192-butyl-6-cyclopropyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

19a) 2-butyl-6-cyclopropylpyrimidin-4(3H)-one

To a solution of methyl 3-cyclopropyl-3-oxopropionate (2.39 g) andpentylamidine hydrochloride (1.68 g) in methanol (20 mL) was added 28%sodium methoxide-methanol solution (5.27 mL), and the mixture wasstirred for 12 hr. The reaction mixture was concentrated, and theresidue was dissolved in water and diethyl ether. The aqueous layer wasseparated, and weakly acidified with 1 M hydrochloric acid. Theprecipitate was collected by filtration and dried under reduced pressureto give the title compound (2.02 g, 78%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.87-0.99 (5H, m), 1.01-1.10 (2H, m),1.29-1.46 (2H, m), 1.61-1.85 (3H, m), 2.61 (2H, t, J=7.5), 6.15 (1H, s),12.89 (1H, br)

19b)4′-[(2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of 2-butyl-6-cyclopropylpyrimidin-4(3H)-one (6 g) and4′-(bromomethyl)biphenyl-2-carbonitrile (9.34 g) in acetonitrile (180mL) was added potassium carbonate (8.63 g), and the mixture was stirredat 50° C. for 12 hr. The insoluble material was filtered off, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound (5.23 g, 44%) as a colorlessviscous substance.

¹H NMR (300 MHz, CDCl₃) δ 0.88 (3H, t, J=7.2), 0.90-1.00 (2H, m),1.03-1.12 (2H, m), 1.24-1.42 (2H, m), 1.57-1.70 (2H, m), 1.73-1.84 (1H,m), 2.62 (2H, t, J=7.5), 5.33 (2H, s), 6.32 (1H, s), 7.28 (2H, d,J=8.1), 7.40-7.56 (4H, m), 7.60-7.68 (1H, m), 7.76 (1H, d, J=7.8)

19c)4′-[(5-bromo-2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(5.22 g) in acetic acid (60 mL) was added bromine (1.39 mL), and themixture was stirred at 70° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution,saturated aqueous sodium hydrogen carbonate and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (5.4 g, 80%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.79 (3H, t, J=7.5), 1.06 (4H, d, J=6.0),1.16-1.32 (2H, m), 1.46-1.61 (2H, m), 2.29-2.41 (1H, m), 2.66 (2H, t,J=7.5), 5.38 (2H, s), 7.30 (2H, d, J=8.4), 7.53-7.65 (4H, m), 7.74-7.84(1H, m), 7.95 (1H, d, J=7.2)

19d)4′-{[2-butyl-4-cyclopropyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) and 2-methyl-2,3-dihydro-1-benzofuran-5-ylboronic acid (0.29 g)in 1,4-dioxane (10 mL) were added 2 M aqueous cesium carbonate solution(2 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05g), and the mixture was stirred at 90° C. for 12 hr under an argonatmosphere. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off through celite. The filtrate waswashed successively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.47 g, 84%) as a pale-yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 0.78-0.87 (2H, m), 0.91 (3H, t, J=7.2),1.10-1.19 (2H, m), 1.30-1.44 (2H, m), 1.48 (3H, d, J=6.3), 1.62-1.76(2H, m), 1.86-1.97 (1H, m), 2.67 (2H, t, J=7.2), 2.86 (1H, dd, J=15.3,7.8), 3.25 (1H, dd, J=15.3, 8.7), 4.87-5.01 (1H, m), 5.34 (2H, s), 6.80(1H, d, J=8.1), 7.17 (1H, d, J=8.1), 7.25-7.78 (1H, m), 7.35 (2H, d,J=8.1), 7.40-7.55 (4H, m), 7.60-7.58 (1H, m), 7.76 (1H, d, J=8.1)

19e)2-butyl-6-cyclopropyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-4-cyclopropyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.46 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.22 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.43 g, 82%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.75-0.87 (5H, m), 0.96-1.17 (2H, m),1.18-1.34 (2H, m), 1.40 (3H, d, J=6.0), 1.48-1.62 (2H, m), 1.72-1.85(1H, m), 2.64 (2H, t, J=7.2), 2.75-2.87 (1H, m), 3.25-3.41 (1H, m),4.85-5.01 (1H, m), 5.31 (2H, s), 6.77 (1H, d, J=8.1), 7.06 (1H, d,J=8.1), 7.18 (1H, s), 7.24 (2H, d, J=8.4), 7.31 (2H, d, J=8.4),7.48-7.61 (2H, m), 7.63-7.74 (2H, m), 12.41 (1H, s)

Example 202-butyl-6-cyclopropyl-5-(4-ethoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

20a)4′-{[2-butyl-4-cyclopropyl-5-(4-ethoxyphenyl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) and 4-ethoxyphenylboronic acid (0.27 g) in 1,4-dioxane (10 mL)were added 2 M aqueous cesium carbonate solution (2 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), andthe mixture was stirred at 90° C. for 12 hr under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.38 g, 70%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.76-0.87 (2H, m), 0.91 (3H, t, J=7.5),1.10-1.20 (2H, m), 1.31-1.47 (5H, m), 1.61-1.75 (2H, m), 1.83-1.96 (1H,m), 2.67 (2H, t, J=7.5), 4.06 (2H, q, J=7.5), 5.35 (2H, s), 6.96 (2H, d,J=8.1), 7.31-7.56 (8H, m), 7.60-7.69 (1H, m), 7.76 (1H, d, J=7.5)

20b)2-butyl-6-cyclopropyl-5-(4-ethoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-4-cyclopropyl-5-(4-ethoxyphenyl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.38 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature. Water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.18 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.38 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.76-1.89 (5H, m), 0.97-1.09 (2H, m),1.19-1.39 (5H, m), 1.47-1.62 (2H, m), 1.70-1.82 (1H, m), 2.64 (2H, t,J=7.2), 4.05 (2H, q, J=7.2), 5.32 (2H, s), 6.98 (2H, d, J=8.4),7.19-7.36 (6H, m), 7.47-7.62 (2H, m), 7.63-7.75 (2H, m), 12.41 (1H, s)

Example 212-butyl-6-ethyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

21a)4′-[(2-butyl-4-ethyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of 2-butyl-6-ethylpyrimidin-4(3H)-one (4 g) and4′-(bromomethyl)biphenyl-2-carbonitrile (6.64 g) in acetonitrile (120mL) was added potassium carbonate (6.1 g), and the mixture was stirredat 50° C. for 12 hr. The insoluble material was filtered off, thefiltrate was concentrated, and the residue was purified by silica gelcolumn chromatography to give the title compound (2.09 g, 25%) as acolorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.2), 1.25 (3H, t, J=7.5),1.31-1.46 (2H, m), 1.61-1.76 (2H, m), 2.56 (2H, q, J=7.5), 2.68 (2H, t,J=7.2), 5.36 (2H, s), 6.29 (1H, s), 7.29 (2H, d, J=8.1), 7.40-7.57 (4H,m), 7.60-7.69 (1H, m), 7.76 (1H, d, J=7.8)

21b)4′-[(5-bromo-2-butyl-4-ethyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(2-butyl-4-ethyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.67 g) in acetic acid (20 mL) was added bromine (0.46 mL), and themixture was stirred at 70° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with 1 M aqueous sodium thiosulfate solution,saturated aqueous sodium hydrogen carbonate and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (1.26 g, 62%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (3H, t, J=7.2), 1.19 (3H, t, J=7.5),1.23-1.36 (2H, m), 1.52-1.67 (2H, m), 2.65-2.78 (4H, m), 5.41 (2H, s),7.32 (2H, d, J=8.4), 7.53-7.64 (4H, m), 7.74-7.84 (1H, m), 7.95 (1H, d,J=7.5)

21c)4′-{[2-butyl-4-ethyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-ethyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) and 2-methyl-2,3-dihydro-1-benzofuran-5-ylboronic acid (0.30 g)in 1,4-dioxane (10 mL) were added 2 M aqueous cesium carbonate solution(2 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05g), and the mixture was stirred at 90° C. for 12 hr under an argonatmosphere. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off through celite. The filtrate waswashed successively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.46 g, 82%) as a pale-yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.2), 1.18 (3H, t, J=7.5),1.35-1.52 (5H, m), 1.68-1.83 (2H, m), 2.49 (2H, q, J=7.5), 2.75 (2H, t,J=7.2), 2.86 (1H, dd, J=15.6, 8.1), 3.34 (1H, dd, J=15.6, 8.7),4.86-5.02 (1H, m), 5.36 (2H, s), 6.79 (1H, d, J=8.4), 7.01 (1H, d,J=8.4), 7.12 (1H, s), 7.36 (2H, d, J=8.1), 7.40-7.57 (4H, m), 7.60-7.69(1H, m), 7.76 (1H, d, J=7.8)

21d)2-butyl-6-ethyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-4-ethyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.46 g) was added, and the mixture was stirred at 90° C. for 16 hr. Themixture was allowed to cool to room temperature. Water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.22 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.45 g, 88%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.5), 1.10 (3H, t, J=7.5),1.38-1.45 (2H, m), 1.40 (3H, d, J=6.0), 1.53-1.68 (2H, m), 2.36 (2H, q,J=7.5), 2.69 (2H, t, J=7.5), 2.74-2.86 (1H, m), 3.26-3.40 (1H, m),4.86-5.00 (1H, m), 5.33 (2H, s), 6.75 (1H, d, J=8.1), 6.96 (1H, d,J=8.1), 7.09 (1H, s), 7.25 (2H, d, J=8.1), 7.32 (2H, d, J=8.1),7.48-7.62 (2H, m), 7.64-7.74 (2H, m), 12.41 (1H, s)

Example 222-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-phenylpyrimidin-4(3H)-one

22a)4′-[(2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of 2-ethoxy-6-methylpyrimidin-4(3H)-one (4.9 g) and4′-(bromomethyl)biphenyl-2-carbonitrile (10.3 g) in acetonitrile (120mL) was added potassium carbonate (5.24 g), and the mixture was stirredat 50° C. for 12 hr. The insoluble material was filtered off, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound (6.15 g, 56%) as a colorlesssolid.

¹H NMR (300 MHz, CDCl₃) δ 1.37 (3H, t, J=7.2), 2.18 (3H, s), 4.43 (2H,q, J=7.2), 5.21 (2H, s), 6.03 (1H, s), 7.39-7.56 (6H, m), 7.58-7.69 (1H,m), 7.75 (1H, d, J=7.8)

22b)4′-[(5-bromo-2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(6.15 g) and sodium acetate (1.46 g) in acetic acid (100 mL) was addedbromine (0.91 mL), and the mixture was stirred for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M aqueous sodiumthiosulfate solution, saturated aqueous sodium hydrogen carbonate andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound (7.12 g,94%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.30 (3H, t, J=7.2), 2.36 (3H, s), 4.42 (2H,q, J=7.2), 5.19 (2H, s), 7.43 (2H, d, J=8.1), 7.51-7.66 (4H, m),7.74-7.85 (1H, m), 7.95 (1H, d, J=7.8)

22c)4′-[(2-ethoxy-4-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1 g) and phenylboronic acid (0.43 g) in 1,4-dioxane (20 mL) were added2 M aqueous cesium carbonate solution (2 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and themixture was stirred at 90° C. for 12 hr under an argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.77 g, 78%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.32 (3H, t, J=7.2), 2.07 (3H, s), 4.45 (2H,q, J=7.2), 5.19 (2H, s), 7.23-7.50 (7H, m), 7.53-7.65 (4H, m), 7.74-7.84(1H, m), 7.95 (1H, d, J=7.8)

22d)2-ethoxy-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.08 g), sodium hydrogencarbonate (1.53 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(2-ethoxy-4-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.77 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature. Water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.44 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.21 g, 24%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (3H, t, J=7.5), 2.06 (3H, s), 4.42 (2H,q, J=7.5), 5.14 (2H, s), 7.21-7.48 (9H, m), 7.48-7.61 (2H, m), 7.62-7.75(2H, m), 12.40 (1H, br)

Example 232-ethoxy-6-methyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

23a)4′-{[2-ethoxy-4-methyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1 g) and 2-methyl-2,3-dihydro-1-benzofuran-5-ylboronic acid (0.63 g) in1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (2mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g),and the mixture was stirred at 90° C. for 12 hr under an argonatmosphere. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off through celite. The filtrate waswashed successively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound (0.77 g, 68%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.31 (3H, t, J=7.2), 1.40 (3H, d, J=6.6),2.07 (3H, s), 2.79 (1H, dd, J=15.6, 7.8), 3.32 (1H, dd, J=15.6, 9.0),4.43 (2H, q, J=7.2), 4.84-4.99 (1H, m), 5.17 (2H, s), 6.73 (1H, d,J=8.1), 6.95 (1H, d, J=8.1), 7.08 (1H, s), 7.45 (2H, d, J=8.4),7.54-7.63 (4H, m), 7.74-7.84 (1H, m), 7.95 (1H, d, J=7.5)

23b)2-ethoxy-6-methyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogencarbonate (1.35 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-ethoxy-4-methyl-5-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.77 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature. Water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.39 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.58 g, 69%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.28 (3H, t, J=7.5), 1.41 (3H, d, J=6.6),2.06 (3H, s), 2.80 (1H, dd, J=15.6, 7.5), 3.33 (1H, dd, J=15.6, 9.0),4.40 (2H, q, J=7.5), 4.81-5.03 (1H, m), 5.13 (2H, s), 6.73 (1H, d,J=8.4), 6.95 (1H, d, J=8.4), 7.07 (1H, s), 7.23-7.40 (4H, m), 7.49-7.61(2H, m), 7.61-7.76 (2H, m), 12.40 (1H, br)

Example 242-butyl-5-(3,5-dimethylisoxazol-4-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

24a)4′-{[2-butyl-5-(3,5-dimethylisoxazol-4-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1 g) and 3,5-dimethylisoxazol-4-ylboronic acid (0.48 g) in 1,4-dioxane(20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and themixture was stirred at 90° C. for 12 hr under an argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (0.32 g, 31%) as a pale-yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5), 1.33-1.50 (2H, m),1.64-1.81 (2H, m), 2.18 (6H, s), 2.29 (3H, s), 2.74 (2H, t, J=7.5), 5.38(2H, s), 7.28-7.35 (2H, m), 7.39-7.58 (4H, m), 7.60-7.70 (1H, m), 7.77(1H, d, J=7.5)

24b)2-butyl-5-(3,5-dimethylisoxazol-4-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.42 g), sodium hydrogencarbonate (0.6 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-5-(3,5-dimethylisoxazol-4-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.32 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.12 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.12 g, 19%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.8), 1.23-1.37 (2H, m),1.53-1.65 (2H, m), 2.05 (3H, s), 2.10 (3H, s), 2.23 (3H, s), 2.70 (2H,t, J=7.5), 5.29-5.45 (2H, m), 7.22 (2H, d, J=8.4), 7.31 (2H, d, J=8.4),7.48-7.61 (2H, m), 7.64-7.74 (2H, m), 12.41 (1H, s)

Example 252-butyl-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

25a)4′-{[2-butyl-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.76 g) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-5-ylboronic acid(0.50 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonatesolution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and themixture was stirred at 90° C. for 12 hr under an argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (0.72 g, 82%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5), 1.35-1.50 (2H, m), 1.49(6H, s), 1.65-1.79 (2H, m), 2.25 (3H, s), 2.76 (2H, t, J=7.5), 3.04 (2H,s), 5.38 (2H, s), 6.76 (1H, d, J=8.1), 7.04 (1H, d, J=8.1), 7.13 (1H,s), 7.35 (2H, d, J=8.1), 7.40-7.56 (4H, m), 7.60-7.68 (1H, m), 7.76 (1H,d, J=7.5)

25b)2-butyl-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.84 g), sodium hydrogencarbonate (1.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.72 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.35 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.68 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.5), 1.22-1.37 (2H, m), 1.43(6H, s), 1.49-1.65 (2H, m), 2.13 (3H, s), 2.68 (2H, t, J=7.5), 3.30 (2H,s), 5.34 (2H, s), 6.72 (1H, d, J=8.1), 7.00 (1H, d, J=8.1), 7.12 (1H,s), 7.25 (2H, d, J=8.1), 7.32 (2H, d, J=8.1), 7.49-7.61 (2H, m),7.64-7.74 (2H, m), 12.43 (1H, s)

Example 262-butyl-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

26a)4′-{[2-butyl-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1 g) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.72 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonatesolution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and themixture was stirred at 90° C. for 12 hr under an argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (0.44 g, 43%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.92 (3H, t, J=7.2), 1.34-1.48 (2H, m),1.64-1.78 (2H, m), 2.49 (3H, s), 2.72 (2H, t, J=7.2), 3.94 (3H, s), 5.40(2H, s), 7.30 (2H, d, J=8.4), 7.40-7.50 (2H, m), 7.53 (2H, d, J=8.4),7.60-7.67 (1H, m), 7.71 (1H, s), 7.75 (1H, d, J=7.5), 7.95 (1H, s)

26b)2-butyl-6-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.7 g), sodium hydrogencarbonate (1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C. for30 min,4′-{[2-butyl-4-methyl-5-(1-methyl-1H-pyrazol-4-yl)-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.44 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature. Water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.24 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.13 g, 27%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.5), 1.21-1.37 (2H, m),1.51-1.65 (2H, m), 2.38 (3H, s), 2.67 (2H, t, J=7.5), 3.87 (3H, s), 5.37(2H, s), 7.22 (2H, d, J=8.4), 7.30 (2H, d, J=8.4), 7.48-7.60 (2H, m),7.63-7.73 (3H, m), 8.05 (1H, s), 12.41 (1H, br)

Example 272-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-phenylpyrimidin-4(3H)-one

27a)4′-{[2-(ethylthio)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of 2-ethylthio-6-methylpyrimidin-4(3H)-one (6.1 g) and4′-(bromomethyl)biphenyl-2-carbonitrile (10.6 g) in acetonitrile (120mL) was added potassium carbonate (5.9 g), and the mixture was stirredat 50° C. for 12 hr. The insoluble material was filtered off, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound (3.83 g, 30%) as a colorlesssolid.

¹H NMR (300 MHz, CDCl₃) δ 1.36 (3H, t, J=7.2), 2.24 (3H, s), 3.18 (2H,q, J=7.2), 5.31 (2H, s), 6.12 (1H, s), 7.38-7.55 (6H, m), 7.59-7.67 (1H,m), 7.75 (1H, d, J=7.8)

27b)4′-{[5-bromo-2-(ethylthio)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[2-(ethylthio)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(3.83 g) and sodium acetate (0.87 g) in acetic acid (40 mL) was addedbromine (0.54 mL), and the mixture was stirred for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M aqueous sodiumthiosulfate solution, saturated aqueous sodium hydrogen carbonate andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound (4.66 g,99%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.38 (3H, t, J=7.2), 2.46 (3H, s), 3.20 (2H,q, J=7.2), 5.34 (2H, s), 7.40-7.53 (6H, m), 7.60-7.68 (1H, m), 7.75 (1H,d, J=7.8)

27c)4′-{[2-(ethylthio)-4-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[5-bromo-2-(ethylthio)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.76 g) and phenylboronic acid (0.32 g) in 1,4-dioxane (10 mL) solutionwere added 2 M aqueous cesium carbonate solution (2 mL) andtetrakis(triphenylphosphine)palladium (0.1 g), and the mixture wasstirred at 90° C. for 12 hr under an argon atmosphere. The reactionmixture was diluted with ethyl acetate, and the insoluble material wasfiltered off through celite. The filtrate was washed successively with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound (0.2 g, 26%)as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.42 (3H, t, J=7.5), 2.20 (3H, s), 3.24 (2H,q, J=7.5), 5.34 (2H, s), 7.28-7.36 (3H, m), 7.36-7.59 (8H, m), 7.59-7.68(1H, m), 7.75 (1H, d, J=8.1)

27d)2-(ethylthio)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.27 g), sodium hydrogencarbonate (0.38 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-(ethylthio)-4-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.20 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (5mL), N,N′-carbonyldiimidazole (0.11 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.11 g, 50%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.32 (3H, t, J=7.2), 2.13 (3H, s), 3.19 (2H,q, J=7.2), 5.26 (2H, s), 7.28-7.47 (9H, m), 7.49-7.61 (2H, m), 7.63-7.75(2H, m), 12.43 (1H, br)

Example 285-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

28a)4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of 6-methyl-2-propylpyrimidin-4(3H)-one (8 g) and4′-(bromomethyl)biphenyl-2-carbonitrile (15.7 g) in acetonitrile (200mL) was added potassium carbonate (14.5 g), and the mixture was stirredat 50° C. for 12 hr. The insoluble material was filtered off, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound (8.44 g, 47%) as a colorlesssolid.

¹H NMR (300 MHz, CDCl₃) δ 0.98 (3H, t, J=7.2), 1.66-1.81 (2H, m), 2.29(3H, s), 2.66 (2H, t, J=7.2), 5.36 (2H, s), 6.29 (1H, s), 7.27 (2H, d,J=8.1), 7.40-7.56 (4H, m), 7.60-7.67 (1H, m), 7.75 (1H, d, J=6.9)

28b)4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(8.44 g) and sodium acetate (2.22 g) in acetic acid (100 mL) was addedbromine (1.39 mL), and the mixture was stirred for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M aqueous sodiumthiosulfate solution, saturated aqueous sodium hydrogen carbonate andsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound (6.68 g,64%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.55-1.70 (2H, m), 2.40(3H, s), 2.67 (2H, t, J=7.2), 5.39 (2H, s), 7.29 (2H, d, J=8.1),7.50-7.63 (4H, m), 7.72-7.82 (1H, m), 7.92 (1H, d, J=7.5)

28c)4′-{[5-(4-isopropoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.0 g) and 4-isopropoxyphenylboronic acid (0.64 g) in 1,4-dioxane (20mL) were added 2 M aqueous cesium carbonate solution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and themixture was stirred at 90° C. for 12 hr under an argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (1.01 g, 89%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.2), 1.34 (6H, d, J=6.0),1.71-1.85 (2H, m), 2.25 (3H, s), 2.72 (2H, t, J=7.2), 4.50-4.63 (1H, m),5.38 (2H, s), 6.93 (2H, d, J=8.7), 7.23 (2H, d, J=8.7), 7.30-7.38 (2H,m), 7.39-7.57 (4H, m), 7.58-7.68 (1H, m), 7.75 (1H, d, J=7.5)

28d)5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.49 g), sodium hydrogencarbonate (3.54 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min,4′-{[5-(4-isopropoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(1.01 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature. Water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (10mL), N,N′-carbonyldiimidazole (0.51 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.75 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.2), 1.29 (6H, d, J=6.3),1.52-1.71 (2H, m), 2.13 (3H, s), 2.66 (2H, t, J=7.2), 4.55-4.73 (1H, m),5.35 (2H, s), 6.93 (2H, d, J=8.1), 7.16-7.37 (6H, m), 7.47-7.62 (2H, m),7.63-7.75 (2H, m), 12.40 (1H, br)

5-(4-Isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following is salts.

-   5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    sodium salt-   5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    potassium salt-   5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    0.5 calcium salt-   5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    hydrochloride-   5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    hydrobromide

Example 295-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

29a)4′-{[5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.0 g) and 2,2-dimethyl-2,3-dihydro-1-benzofuran-5-ylboronic acid (0.68g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonatesolution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and themixture was stirred at 90° C. for 12 hr under an argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (1.03 g, 89%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.2), 1.49 (6H, s), 1.69-1.85(2H, m), 2.25 (3H, s), 2.71 (2H, t, J=7.2), 3.04 (2H, s), 5.37 (2H, s),6.76 (1H, d, J=8.4), 7.03 (1H, d, J=8.4), 7.13 (1H, s), 7.28-7.38 (2H,m), 7.39-7.57 (4H, m), 7.59-7.68 (1H, m), 7.76 (1H, d, J=7.5)

29b)5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.49 g), sodium hydrogencarbonate (3.54 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min,4′-{[5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(1.03 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature. Water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (10mL), N,N′-carbonyldiimidazole (0.51 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.18 g, 16%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.2), 1.43 (6H, s), 1.55-1.70(2H, m), 2.13 (3H, s), 2.66 (2H, t, J=7.2), 3.02 (2H, s), 5.34 (2H, s),6.72 (1H, d, J=7.8), 7.11 (1H, d, J=7.8), 7.12 (1H, s), 7.24 (2H, d,J=8.4), 7.31 (2H, d, J=8.4), 7.49-7.60 (2H, m), 7.63-7.73 (2H, m), 12.39(1H, s)

Example 305-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

30a)4′-{[5-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.0 g) and (2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronic acid (0.73g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonatesolution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and themixture was stirred at 90° C. for 12 hr under an argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washedsuccessively with 1 M hydrochloric acid, saturated aqueous sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (0.58 g, 49%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.03 (3H, t, J=7.2), 1.35 (6H, s), 1.72-1.86(4H, m), 2.25 (3H, s), 2.67-2.74 (2H, m), 2.80 (2H, t, J=6.6), 5.38 (2H,s), 6.81 (1H, d, J=8.1), 7.00-7.08 (2H, m), 7.34 (2H, d, J=8.1),7.40-7.56 (4H, m), 7.60-7.68 (1H, m), 7.76 (1H, d, J=7.8)

30b)5-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.37 g), sodium hydrogencarbonate (1.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.58 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature. Water was added to thereaction mixture, and the precipitate was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (10mL), N,N′-carbonyldiimidazole (0.28 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound ascolorless crystals (0.46 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.2), 1.30 (6H, s), 1.55-1.70(2H, m), 1.78 (2H, t, J=6.6), 2.13 (3H, s), 2.60-2.70 (2H, m), 2.74 (2H,t, J=6.6), 5.34 (2H, s), 6.72 (1H, d, J=8.1), 6.95-7.05 (2H, m),7.21-7.35 (4H, m), 7.49-7.61 (2H, m), 7.63-7.74 (2H, m), 12.40 (1H, br)

Example 316-butyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

31a)4′-({4-butyl-1-[2-(4-methoxyphenyl)-2-oxoethyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min,2-bromo-1-(4-methoxyphenyl)ethanone (0.77 g) was added, and the mixturewas stirred at room temperature for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.68 g, 48%).

¹H NMR (300 MHz, CDCl₃) δ 0.88 (3H, t, J=7.3), 1.29-1.43 (2H, m),1.45-1.61 (2H, m), 2.45 (3H, s), 2.65-2.73 (2H, m), 3.87 (3H, s), 4.13(2H, s), 5.62 (2H, s), 6.93-6.99 (2H, m), 7.32-7.52 (6H, m), 7.58-7.66(1H, m), 7.75 (1H, dd, J=7.7, 0.9), 7.92-8.00 (2H, m)

31b)6-butyl-3-[2-(4-methoxyphenyl)-2-oxoethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.12 g), sodium hydrogencarbonate (1.69 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[2-(4-methoxyphenyl)-2-oxoethyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.68 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.19 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.051g, 7%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.4), 1.20-1.38 (2H, m),1.40-1.59 (2H, m), 2.35 (3H, s), 2.51-2.57 (2H, m), 3.76-3.93 (5H, m),5.60 (2H, s), 7.13 (2H, d, J=9.0), 7.17-7.34 (4H, m), 7.44-7.58 (2H, m),7.59-7.72 (2H, m), 8.08 (2H, d, J=8.9), 12.41 (1H, br)

Example 32

6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 2-(bromomethyl)thiophene (5 g)was added, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue obtained by silica gelcolumn chromatography was dissolved in dimethyl sulfoxide (5 mL), andadded to a mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.66 g) and dimethyl sulfoxide (10 mL) previously stirred at40° C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr.The mixture was diluted with ethyl acetate, washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.26 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.41 g,61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (3H, t, J=7.3), 1.21-1.32 (2H, m),1.35-1.47 (2H, m), 2.43-2.49 (2H, m), 2.54 (3H, s), 3.89 (2H, s), 5.38(2H, s), 6.99 (1H, dd, J=5.1, 3.4), 7.16-7.28 (5H, m), 7.44-7.58 (3H,m), 7.62-7.72 (2H, m), 12.39 (1H, s)

6-Butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one    sodium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one    potassium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one    hydrochloride-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one    hydrobromide

Example 336-butyl-3-(2,2-dimethylpropyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

33a)4′-{[4-butyl-1-(2,2-dimethylpropyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), cesium carbonate (1.82 g), 1-iodo-2,2-dimethylpropane (0.74 mL)and N,N-dimethylacetamide (10 mL) was stirred at 130° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.36 g,30%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.00 (9H, s), 1.32-1.44(2H, m), 1.51-1.63 (2H, m), 2.51-2.62 (5H, m), 3.80-4.10 (4H, m),7.31-7.51 (6H, m), 7.57-7.66 (1H, m), 7.74 (1H, dd, J=7.7, 0.9)

33b)6-butyl-3-(2,2-dimethylpropyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.7 g), sodium hydrogencarbonate (1.06 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,2-dimethylpropyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.36 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.13 g,31%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 0.91 (9H, s), 1.20-1.34(2H, m), 1.38-1.52 (2H, m), 2.41-2.48 (2H, m), 3.32 (3H, s), 3.84 (2H,s), 3.95 (2H, br), 7.16-7.26 (4H, m), 7.45-7.58 (2H, m), 7.62-7.71 (2H,m), 12.37 (1H, s)

Example 346-butyl-3-(2-hydroxyethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

34a)4′-{[4-butyl-1-(2-hydroxyethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 2-bromoethanol (0.40 mL) wasadded, and the mixture was stirred at room temperature for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.26 g,23%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3), 1.31-1.45 (2H, m),1.53-1.62 (2H, m), 2.58 (3H, s), 2.69-2.79 (2H, m), 3.17 (1H, t, J=5.2),3.84 (2H, d, J=3.6), 4.03 (2H, s), 4.45-4.53 (2H, m), 7.21-7.28 (2H, m),7.39-7.51 (4H, m), 7.59-7.67 (1H, m), 7.75 (1H, dd, J=7.4, 1.0)

34b)6-butyl-3-(2-hydroxyethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-{[4-butyl-1-(2-hydroxyethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.26 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.45 mL),2,6-lutidine (0.25 mL) and tetrahydrofuran (10 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (10 mL), and added to a mixture ofhydroxylammonium chloride (0.4 g), sodium hydrogen carbonate (0.61 g)and dimethyl sulfoxide (10 mL) previously stirred at 40° C. for 30 min.The reaction mixture was stirred at 90° C. for 16 hr. The mixture wasdiluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.094 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.08 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was dissolved in tetrahydrofuran (20 mL).Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.08 mL)was added thereto, and the mixture was stirred at room temperature for 3hr. The reaction mixture was extracted with 1 M hydrochloric acid andethyl acetate, and the ethyl acetate layer was washed with saturatedbrine and concentrated. The residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.055g, 19%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.21-1.33 (2H, m),1.39-1.50 (2H, m), 2.45 (3H, s), 2.57-2.66 (2H, m), 3.66-3.73 (2H, m),3.98 (2H, s), 4.30-4.37 (2H, m), 4.79-4.89 (1H, m), 7.18-7.26 (4H, m),7.46-7.58 (2H, m), 7.62-7.71 (2H, m), 12.36 (1H, s)

Example 352-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(2-thienylmethyl)pyrimidin-4(3H)-one

35a)4′-{[2-methyl-6-oxo-4-propyl-1-(2-thienylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 2-(bromomethyl)thiophene (4.5 g)was added, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.74 g, 58%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.3), 1.53-1.65 (2H, m),2.51-2.59 (2H, m), 2.61 (3H, s), 4.00 (2H, s), 5.38 (2H, s), 6.96 (1H,dd, J=5.1, 3.6), 7.07 (1H, dd, J=3.4, 0.9), 7.23-7.28 (1H, m), 7.34-7.52(6H, m), 7.58-7.66 (1H, m), 7.74 (1H, dd, J=7.7, 0.9)

35b)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(2-thienylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.41 g), sodium hydrogencarbonate (2.13 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-6-oxo-4-propyl-1-(2-thienylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.74 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.33 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.39 g,46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.40-1.53 (2H, m), 2.45(2H, dd, J=8.6, 6.7), 2.54 (3H, s), 3.90 (2H, s), 5.38 (2H, s), 6.99(1H, dd, J=5.1, 3.4), 7.16-7.28 (5H, m), 7.44-7.58 (3H, m), 7.63-7.72(2H, m), 12.38 (1H, s)

Example 366-butyl-3-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

36a)4′-{[4-butyl-1-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-bromo-3,3-dimethylbutan-2-one(0.75 g) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue obtained by silica gelcolumn chromatography was dissolved in methanol (10 mL), sodiumborohydride (0.092 g) was added, and the mixture was stirred at roomtemperature for 3 hr. The reaction mixture was concentrated, and theresidue was extracted with ethyl acetate and saturated aqueous ammoniumchloride solution. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.21 g, 16%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.2), 1.03 (9H, s), 1.31-1.44(2H, m), 1.49-1.65 (2H, m), 2.53-2.63 (5H, m), 3.64 (1H, dd, J=10.3,1.8), 3.96 (2H, s), 4.01-4.11 (1H, m), 4.17-4.28 (1H, m), 7.29-7.36 (2H,m), 7.37-7.50 (4H, m), 7.58-7.66 (1H, m), 7.74 (1H, dd, J=7.7, 1.1)

36b)6-butyl-3-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-{[4-butyl-1-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.21 g), tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.36 mL),2,6-lutidine (0.16 mL) and tetrahydrofuran (10 mL) was stirred at 0° C.for 3 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and added to a mixture of hydroxylammoniumchloride (0.97 g), sodium hydrogen carbonate (1.47 g) and dimethylsulfoxide (10 mL) previously stirred at 40° C. for 30 min. The reactionmixture was stirred at 90° C. for 16 hr. The mixture was diluted withethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (20 mL),N,N′-carbonyldiimidazole (0.14 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3.5 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 M hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography to give the title compound as colorless amorphouscrystals (0.2 g, 55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.2), 0.93 (9H, s), 1.22-1.33(2H, m), 1.38-1.50 (2H, m), 2.41-2.48 (2H, m), 2.55 (3H, s), 3.42-3.51(1H, m), 3.63 (1H, dd, J=13.2, 10.5), 3.84 (2H, q, J=15.1), 4.24 (1H, d,J=11.9), 5.03 (1H, d, J=5.7), 7.18-7.27 (4H, m), 7.47-7.58 (2H, m),7.61-7.72 (2H, m), 12.39 (1H, br)

Example 37

6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.19 g), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.18 g) and methylene chloride (10 mL) was stirred at room temperaturefor 2 hr. A saturated aqueous sodium hydrogen carbonate solution andsodium thiosulfate were added to the reaction mixture, and the mixturewas stirred at room temperature for 2 hr and extracted with chloroform.The chloroform layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.13 g,69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.22 (9H, s), 1.25-1.34(2H, m), 1.38-1.51 (2H, m), 2.28 (3H, s), 2.45-2.49 (2H, m), 3.83 (2H,s), 5.16 (2H, s), 7.21 (4H, s), 7.52 (2H, dd, J=16.3, 7.6), 7.62-7.72(2H, m), 12.38 (1H, s)

6-Butyl-3-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 383-(1-benzothien-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

38a)4′-{[1-(1-benzothien-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.23 g), tributylphosphine(1.52 mL), 1-benzothien-2-ylmethanol (0.56 g) and tetrahydrofuran (50mL) was stirred at room temperature for 4 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.55 g, 45%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3), 1.31-1.43 (2H, m),1.49-1.57 (2H, m), 2.55-2.62 (2H, m), 2.64 (3H, s), 4.02 (2H, s), 5.48(2H, s), 7.24-7.28 (2H, m), 7.30-7.34 (2H, m), 7.37-7.51 (5H, m),7.57-7.68 (1H, m), 7.68-7.81 (3H, m)

38b)3-(1-benzothien-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogencarbonate (1.38 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[1-(1-benzothien-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.55 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.21 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.31 g,51%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.20-1.33 (2H, m),1.36-1.48 (2H, m), 2.43-2.49 (2H, m), 2.57 (3H, s), 3.92 (2H, s), 5.51(2H, s), 7.21-7.30 (4H, m), 7.30-7.39 (2H, m), 7.45-7.58 (3H, m),7.64-7.71 (2H, m), 7.79-7.86 (1H, m), 7.89-7.96 (1H, m), 12.39 (1H, s)

Example 396-butyl-3-[(5-chloro-2-thienyl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

39a)4′-({4-butyl-1-[(5-chloro-2-thienyl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min,2-chloro-5-(chloromethyl)thiophene (2.39 g) was added, and the mixturewas stirred at room temperature for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,and the residue was purified by silica gel column chromatography to givethe title compound as a colorless solid (0.63 g, 45%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3), 1.37 (2H, dq, J=7.3,7.1), 1.48-1.59 (2H, m), 2.53-2.66 (5H, m), 3.99 (2H, s), 5.24 (2H, s),6.76 (1H, d, J=3.8), 6.85 (1H, d, J=3.8), 7.34-7.51 (6H, m), 7.55-7.67(1H, m), 7.74 (1H, d, J=7.3)

39b)6-butyl-3-[(5-chloro-2-thienyl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.64 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[(5-chloro-2-thienyl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.64 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.32 g,45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (3H, t, J=7.3), 1.20-1.32 (2H, m),1.35-1.46 (2H, m), 2.43-2.50 (2H, m), 2.55 (3H, s), 3.89 (2H, s), 5.28(2H, s), 7.00 (1H, d, J=3.8), 7.11 (1H, d, J=3.8), 7.19-7.28 (4H, m),7.47-7.58 (2H, m), 7.63-7.72 (2H, m), 12.38 (1H, br)

Example 406-butyl-2-methyl-3-[(3-methyloxetan-3-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

40a)4′-({4-butyl-2-methyl-1-[(3-methyloxetan-3-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.44 g), tributylphosphine(1.78 mL), (3-methyloxetan-3-yl)methanol (0.44 g) and tetrahydrofuran(50 mL) was stirred at room temperature for 4 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.78 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.2), 1.34-1.46 (2H, m),1.55-1.69 (2H, m), 2.17 (3H, s), 2.59 (3H, s), 2.71-2.82 (2H, m), 4.02(2H, s), 4.26-4.48 (6H, m), 7.20 (2H, d, J=8.1), 7.38-7.52 (4H, m),7.57-7.67 (1H, m), 7.75 (1H, d, J=7.7)

40b)6-butyl-2-methyl-3-[(3-methyloxetan-3-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.47 g), sodium hydrogencarbonate (2.23 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-1-[(3-methyloxetan-3-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.78 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless powder (0.048g, 5%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.4), 1.20 (3H, s), 1.25-1.37(2H, m), 1.44-1.57 (2H, m), 2.47 (3H, s), 2.65-2.75 (2H, m), 3.96 (2H,s), 4.20 (2H, d, J=6.0), 4.31-4.39 (4H, m), 7.13-7.24 (4H, m), 7.46 (1H,d, J=7.7), 7.54 (1H, dt, J=7.5, 1.3), 7.62-7.72 (2H, m), 12.38 (1H, br)

Example 416-butyl-3-[(6-fluoro-1,2-benzisoxazol-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

41a) 6-fluoro-3-methyl-1,2-benzisoxazole

A mixture of 1-(4-fluoro-2-hydroxyphenyl)ethanone (20 g),hydroxyammonium chloride (18.1 g), sodium acetate (16 g) and methanol(500 mL) was stirred at 60° C. for 1 hr. The reaction mixture was addedto ice water, and the obtained crystallized product was collected byfiltration and dissolved in tetrahydrofuran (400 mL).N,N′-carbonyldiimidazole (22.5 g) and then a solution of triethylamine(22.3 mL) in tetrahydrofuran (100 mL) were added, and the mixture wasstirred at 70° C. for 1 hr. The reaction mixture was diluted withdiethyl ether, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give the title compound as colorless crystals (13.7g, 70%).

¹H NMR (300 MHz, CDCl₃) δ 2.34 (3H, s), 6.52-6.74 (2H, m), 7.39 (1H, dd,J=8.8, 6.3)

41b)6-butyl-3-[(6-fluoro-1,2-benzisoxazol-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a mixture of 6-fluoro-3-methyl-1,2-benzisoxazole (2.0 g) and carbontetrachloride (100 mL) was added a mixture of N-bromosuccinimide (2.58g) and benzoyl peroxide (0.43 g) at 80° C., and the mixture was stirredat the same temperature for 4 hr. The reaction mixture was concentratedunder reduced pressure, and the obtained residue was extracted withwater and ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure, and the obtained oil was added toa mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL)previously stirred at room temperature for 10 min. The reaction mixturewas stirred at room temperature for 16 hr. and diluted with ethylacetate. The mixture was washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and added to a mixture of hydroxylammoniumchloride (1.03 g), sodium hydrogen carbonate (1.65 g) and dimethylsulfoxide (10 mL) previously stirred at 40° C. for 30 min. The reactionmixture was stirred at 90° C. for 16 hr. and diluted with ethyl acetate.The mixture was washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (20 mL),N,N′-carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.14 g,25%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.4), 1.22-1.38 (2H, m),1.39-1.54 (2H, m), 2.50-2.55 (2H, m), 2.57 (3H, s), 3.88 (2H, s), 5.69(2H, s), 7.17-7.27 (4H, m), 7.33 (1H, dt, J=9.1, 2.3), 7.46-7.59 (2H,m), 7.62-7.71 (2H, m), 7.76 (1H, dd, J=9.0, 2.3), 7.97 (1H, dd, J=8.9,5.3), 12.39 (1H, br)

Example 42

3-(1-adamantylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-(bromomethyl)adamantane (1.9g) was added, and the mixture was stirred at 150° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by silica gel columnchromatography was dissolved in dimethyl sulfoxide (5 mL), and added toa mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.78 g) and dimethyl sulfoxide (10 mL) previously stirred at40° C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,and diluted with ethyl acetate. The mixture was washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.21 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.11 g,19%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.22-1.34 (2H, m),1.39-1.48 (2H, m), 1.49-1.67 (12H, m), 1.91 (3H, s), 2.44 (2H, m), 2.50(3H, s), 3.57-4.13 (4H, m), 7.16-7.26 (4H, m), 7.44-7.57 (2H, m),7.61-7.71 (2H, m), 12.37 (1H, br)

3-(1-Adamantylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(1-adamantylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   3-(1-adamantylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   3-(1-adamantylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   3-(1-adamantylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   3-(1-adamantylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 436-butyl-2-methyl-3-(2-methyl-2-phenylpropyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

43a)4′-{[4-butyl-2-methyl-1-(2-methyl-2-phenylpropyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), cyanomethylene tri-n-butylphosphorane (1 g),2-methyl-2-phenylpropan-1-ol (0.63 g) and toluene (30 mL) was stirred at100° C. for 16 hr. The reaction mixture was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.13 g,10%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.2), 1.30-1.48 (8H, m),1.49-1.63 (2H, m), 1.70 (3H, s), 2.51-2.61 (2H, m), 3.94-4.00 (4H, m),7.19-7.51 (11H, m), 7.56-7.66 (1H, m), 7.73 (1H, dd, J=7.7, 1.3)

43b)6-butyl-2-methyl-3-(2-methyl-2-phenylpropyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.27 g), sodium hydrogencarbonate (0.45 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(2-methyl-2-phenylpropyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.13 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.052 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.044 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.036g, 24%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.20-1.48 (10H, m),1.72 (3H, s), 2.38-2.48 (2H, m), 3.87 (2H, s), 4.18 (2H, s), 7.19-7.34(8H, m), 7.46-7.57 (2H, m), 7.62-7.73 (2H, m), 12.38 (1H, br)

Example 443-[2-(1-adamantyl)-2-hydroxyethyl]-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

44a)4′-{[1-(2-(1-adamantyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-(1-adamantyl)-2-bromoethanone(1.08 g) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue obtained by silica gelcolumn chromatography was dissolved in methanol (20 mL), sodiumborohydride (0.12 g) was added, and the mixture was stirred at roomtemperature for 3 hr. The reaction mixture was concentrated, and theresidue was extracted with ethyl acetate and saturated aqueous ammoniumchloride solution. The ethyl acetate layer was washed with saturatedbrine, and concentrated. The obtained residue was dissolved intetrahydrofuran (20 mL), and tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.47 mL) and 2,6-lutidine (0.24 mL) wereadded at 0° C. The reaction mixture was stirred at 0° C. for 3 hr, anddiluted with ethyl acetate. The mixture was washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.56 g, 31%).

¹H NMR (300 MHz, CDCl₃) δ 0.87-0.93 (18H, m), 1.31-1.44 (2H, m),1.47-1.82 (14H, m), 2.01 (3H, br), 2.56-2.70 (5H, m), 3.64-3.78 (1H, m),3.81-3.91 (1H, m), 4.43 (1H, d, J=13.0), 7.33-7.50 (6H, m), 7.57-7.65(1H, m), 7.74 (1H, d, J=7.7)

44b)3-[2-(1-adamantyl)-2-hydroxyethyl]-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.90 g), sodium hydrogencarbonate (1.44 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[1-(2-(1-adamantyl)-2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.56 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3.9 mL) wasadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was extracted with 1 M hydrochloric acid and ethylacetate, and the ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.11 g,24%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.4), 1.20-1.33 (2H, m),1.36-1.48 (2H, m), 1.51-1.74 (12H, m), 1.96 (3H, s), 2.39-2.48 (2H, m),2.52 (3H, s), 3.25-3.31 (1H, m), 3.62-3.72 (1H, m), 3.74-3.93 (2H, m),4.24 (1H, d, J=12.1), 4.88 (1H, d, J=5.8), 7.17-7.28 (4H, m), 7.45-7.59(2H, m), 7.61-7.73 (2H, m), 12.38 (1H, s)

Example 45

3-[2-(1-adamantyl)-2-oxoethyl]-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of3-[2-(1-adamantyl)-2-hydroxyethyl]-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.078 g), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.067 g) and methylene chloride (10 mL) was stirred at room temperaturefor 2 hr. A saturated aqueous sodium hydrogen carbonate solution andsodium thiosulfate were added to the reaction mixture. The mixture wasstirred at room temperature for 2 hr and extracted with chloroform. Thechloroform layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.057g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.4), 1.19-1.35 (2H, m),1.39-1.55 (2H, m), 1.63-1.79 (6H, m), 1.82-1.96 (6H, m), 2.03 (3H, s),2.26 (3H, s), 2.43-2.48 (2H, m), 3.83 (2H, s), 5.13 (2H, s), 7.20 (4H,s), 7.45-7.58 (2H, m), 7.60-7.73 (2H, m), 12.38 (1H, s)

Example 466-butyl-3-(4-fluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

46a)4′-{[4-butyl-1-(4-fluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-(bromomethyl)-4-fluorobenzene(0.52 mL) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.76 g, 58%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.31-1.46 (2H, m),1.51-1.61 (2H, m), 2.46 (3H, s), 2.56-2.66 (2H, m), 4.00 (2H, s), 5.26(2H, s), 6.98-7.10 (2H, m), 7.15-7.22 (2H, m), 7.33-7.52 (6H, m),7.58-7.66 (1H, m), 7.75 (1H, d, J=8.5)

46b)6-butyl-3-(4-fluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogencarbonate (2.74 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-fluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.32 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.55 g,65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.4), 1.21-1.36 (2H, m),1.38-1.56 (2H, m), 2.39 (3H, s), 2.43-2.51 (2H, m), 3.90 (2H, s), 5.26(2H, s), 7.14-7.36 (8H, m), 7.44-7.59 (2H, m), 7.60-7.76 (2H, m), 12.40(1H, s)

Example 473-benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

47a)4′-[(1-benzyl-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, (bromomethyl)benzene (0.67 mL)was added, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.64 g, 51%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.32-1.45 (2H, m),1.52-1.62 (2H, m), 2.45 (3H, s), 2.55-2.67 (2H, m), 4.01 (2H, s), 5.30(2H, s), 7.16-7.23 (2H, m), 7.26-7.41 (6H, m), 7.43-7.51 (3H, m), 7.61(1H, dd, J=7.6, 1.2), 7.74 (1H, dd, J=7.7, 0.9)

47b)3-benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.49 g), sodium hydrogencarbonate (2.40 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(1-benzyl-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.64 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.28 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.36 g,49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.23-1.38 (2H, m),1.37-1.56 (2H, m), 2.38 (3H, s), 2.46-2.57 (2H, m), 3.91 (2H, s), 5.29(2H, s), 7.13-7.42 (9H, m), 7.47-7.61 (2H, m), 7.61-7.74 (2H, m), 12.39(1H, s)

3-Benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   3-benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   3-benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   3-benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   3-benzyl-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 486-butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

48a)4′-{[4-butyl-1-(cyclohexylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, (bromomethyl)cyclohexane (0.70mL) was added, and the mixture was stirred at room temperature for 16hr. The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.38 g, 30%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.2), 0.99-1.26 (4H, m),1.32-1.43 (2H, m), 1.50-1.78 (8H, m), 1.79-1.92 (1H, m), 2.53 (3H, s),2.54-2.61 (2H, m), 3.86 (2H, d, J=7.0), 3.95 (2H, s), 7.31-7.49 (6H, m),7.57-7.65 (1H, m), 7.74 (1H, dd, J=7.7, 0.9)

48b)6-butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogencarbonate (1.41 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(cyclohexylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.38 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.14 g,33%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 0.97-1.90 (15H, m),2.40-2.50 (5H, m), 3.84 (4H, s), 7.03-7.27 (4H, m), 7.43-7.58 (2H, m),7.60-7.72 (2H, m), 12.37 (1H, s)

6-Butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    dihydrochloride-   6-butyl-3-(cyclohexylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    dihydrobromide

Example 49

6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-phenylethyl)pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, (2-bromoethyl)benzene (0.76 mL)was added, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue obtained by silica gelcolumn chromatography was dissolved in dimethyl sulfoxide (5 mL), andadded to a mixture of hydroxylammonium chloride (0.9 g), sodium hydrogencarbonate (1.45 g) and dimethyl sulfoxide (10 mL) previously stirred at40° C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,and diluted with ethyl acetate. The mixture was washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.14 g,31%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.2), 1.17-1.33 (2H, m),1.35-1.50 (2H, m), 2.37 (3H, s), 2.41-2.48 (2H, m), 2.94 (2H, t, J=7.5),3.87 (2H, s), 4.14 (2H, t, J=8.1), 7.18-7.36 (9H, m), 7.47-7.57 (2H, m),7.61-7.73 (2H, m), 12.38 (1H, br)

Example 506-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one

50a)4′-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), potassium carbonate (0.77 g), 2-(bromomethyl)pyridinehydrobromide (1.06 g) and N,N-dimethylformamide (10 mL) was stirred at50° C. for 4 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.87 g,69%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.4), 1.30-1.44 (2H, m),1.49-1.64 (2H, m), 2.56-2.65 (5H, m), 3.98 (2H, s), 5.38 (2H, s),7.16-7.29 (2H, m), 7.32-7.52 (6H, m), 7.56-7.69 (2H, m), 7.74 (1H, dd,J=7.7, 0.9), 8.51-8.57 (1H, m)

50b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.02 g), sodium hydrogencarbonate (3.24 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.87 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas adjusted to pH 5 with water and 1 M hydrochloric acid, and extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as colorlesscrystals (0.076 g, 8%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.3), 1.22-1.38 (2H, m),1.39-1.54 (2H, m), 2.42-2.52 (5H, m), 3.85 (2H, s), 5.34 (2H, s),7.13-7.25 (4H, m), 7.25-7.40 (2H, m), 7.44-7.60 (2H, m), 7.59-7.76 (2H,m), 7.74-7.86 (1H, m), 8.42-8.55 (1H, m), 12.38 (1H, s)

6-Butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one    sodium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one    potassium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one    hydrochloride-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one    hydrobromide

Example 516-butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

51a)4′-{[4-butyl-1-(2,2-dimethylpropyl)-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(5 g), cesium carbonate (8.4 g), 1-iodo-2,2-dimethylpropane (3.4 mL) andN,N-dimethylacetamide (50 mL) was stirred at 130° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.76 g,30%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.4), 0.98 (9H, s), 1.30-1.45(2H, m), 1.52-1.67 (2H, m), 2.57-2.66 (2H, m), 3.38 (3H, s), 3.97 (2H,s), 4.13 (2H, br), 4.54 (2H, br), 7.31-7.50 (6H, m), 7.57-7.65 (1H, m),7.74 (1H, dd, J=7.7, 0.8)

51b)6-butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (4.01 g), sodium hydrogencarbonate (6.50 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,2-dimethylpropyl)-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (0.75 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.63 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.78 g,39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 0.90 (9H, s), 1.20-1.36(2H, m), 1.41-1.55 (2H, m), 2.45-2.59 (5H, m), 3.88 (2H, s), 4.00 (2H,s), 4.47 (2H, s), 7.15-7.29 (4H, m), 7.52 (2H, dd, J=18.3, 7.5),7.61-7.75 (2H, m), 12.37 (1H, s)

6-Butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 526-butyl-3-(2-hydroxy-2-phenylethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

52a)4′-{[4-butyl-2-methyl-6-oxo-1-(2-oxo-2-phenylethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.5 g), sodium hydride (0.25 g) and N,N-dimethylformamide (30 mL) wasstirred at room temperature for 10 min, 2-bromo-1-phenylethanone (1.25g) was added, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.87 g, 43%).

¹H NMR (300 MHz, CDCl₃) δ 0.92 (3H, t, J=7.3), 1.31-1.49 (2H, m),1.53-1.68 (2H, m), 2.41 (3H, s), 2.58-2.67 (2H, m), 3.97 (2H, s), 5.51(2H, s), 7.31-7.68 (10H, m), 7.73 (1H, dd, J=7.7, 1.3), 8.00-8.08 (2H,m)

52b)4′-{[4-butyl-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-butyl-2-methyl-6-oxo-1-(2-oxo-2-phenylethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.87 g), sodium borohydride (0.21 g) and methanol (25 mL) was stirredat room temperature for 3 hr. The reaction mixture was concentrated. Theresidue was extracted with ethyl acetate and saturated aqueous ammoniumchloride solution. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The obtained residue was dissolved intetrahydrofuran (20 mL), and 2,6-lutidine (0.50 mL) andtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.98 mL) were addedat 0° C. The reaction mixture was stirred at 0° C. for 3 hr, and dilutedwith ethyl acetate. The mixture was washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.73 g, 29%).

¹H NMR (300 MHz, CDCl₃) δ −0.29-0.22 (6H, m), 0.78 (9H, s), 0.92 (3H, t,J=7.3), 1.32-1.45 (2H, m), 1.50-1.64 (2H, m), 2.51-2.75 (5H, m), 3.75(1H, br), 3.98 (2H, dd, J=25.6, 15.1), 4.33-4.43 (1H, m), 5.22 (1H, dd,J=9.9, 2.9), 7.28-7.50 (11H, m), 7.58-7.65 (1H, m), 7.74 (1H, dd, J=7.7,0.9)

52c)6-butyl-3-(2-hydroxy-2-phenylethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.29 g), sodium hydrogencarbonate (2.07 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.73 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3.7 mL) wasadded, and the mixture was stirred at 70° C. for 6 hr. The reactionmixture was extracted with 1 M hydrochloric acid and ethyl acetate, andthe ethyl acetate layer was washed with saturated brine andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.37 g,56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.20-1.36 (2H, m),1.35-1.53 (2H, m), 2.39-2.62 (5H, m), 3.78-3.99 (3H, m), 4.16 (1H, dd,J=13.7, 3.1), 4.86-5.07 (1H, m), 5.77 (1H, d, J=4.5), 7.16-7.33 (5H, m),7.34-7.47 (4H, m), 7.46-7.59 (2H, m), 7.62-7.77 (2H, m), 12.39 (1H, s)

Example 536-(methoxymethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one

53a) methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-4-methoxy-3-oxobutanoate

A solution of methyl 4-methoxy-3-oxobutyrate (10.7 g) in tetrahydrofuran(150 mL) was added to a mixture of sodium hydride (1.91 g) andtetrahydrofuran (150 mL) at room temperature, and the mixture wasstirred at room temperature for 30 min.4′-(Bromomethyl)biphenyl-2-carbonitrile (10 g) was added to the reactionmixture, and the reaction mixture was stirred at room temperature for 3days. The reaction mixture was concentrated. To the residue were added5% aqueous potassium hydrogen sulfate solution and then ethyl acetate,and the mixture was extracted. The ethyl acetate layer was washed withsaturated brine and concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound as a colorless oil(12.1 g, 98%).

¹H NMR (300 MHz, CDCl₃) δ 3.25 (2H, t, J=7.4), 3.34 (3H, s), 3.71 (3H,s), 3.88-4.12 (3H, m), 7.25-7.34 (2H, m), 7.39-7.51 (4H, m), 7.60-7.67(1H, m), 7.75 (1H, d, J=7.7)

53b)4′-{[4-(methoxymethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of acetamidine hydrochloride (3.4 g) in methanol (30 mL)was added sodium methoxide (28% methanol solution, 10.3 g) at 0° C., asolution of methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-4-methoxy-3-oxobutanoate in methanol(60 mL)-1,4-dioxane (20 mL) was added, and the mixture was stirred atroom temperature for 16 hr. The reaction mixture was concentrated, andwater (50 mL) and 50% aqueous acetic acid solution were added to theresidue and adjusted to pH 5. The obtained crystallized product wascollected by filtration and washed with water to give the title compoundas colorless crystals (5.27 g, 86%).

¹H NMR (300 MHz, DMSO-d₆) δ 2.27 (3H, s), 3.27 (3H, s), 3.89 (2H, s),4.30 (2H, s), 7.33-7.39 (2H, m), 7.45-7.51 (2H, m), 7.53-7.61 (2H, m),7.77 (1H, dt, J=7.7, 1.0), 7.93 (1H, d, J=7.7), 12.49 (1H, s)

53c)4′-{[4-(methoxymethyl)-2-methyl-6-oxo-1-(2-thienylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-(methoxymethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 2-(bromomethyl)thiophene (4.5 g)was added, and the mixture was stirred at room temperature for 16 hr.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.68 g, 53%).

¹H NMR (300 MHz, CDCl₃) δ 2.66 (3H, s), 3.44 (3H, s), 4.06 (2H, s), 4.38(2H, s), 5.39 (2H, s), 6.95 (1H, dd, J=5.1, 3.4), 7.06 (1H, dd, J=3.5,1.0), 7.22-7.29 (1H, m), 7.37-7.43 (3H, m), 7.43-7.50 (3H, m), 7.62 (1H,dt, J=7.7, 1.4), 7.74 (1H, dd, J=7.7, 0.9)

53d)6-(methoxymethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-thienylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.29 g), sodium hydrogencarbonate (1.94 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-(methoxymethyl)-2-methyl-6-oxo-1-(2-thienylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.68 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.3 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.4 g,52%).

¹H NMR (300 MHz, DMSO-d₆) δ 2.56 (3H, s), 3.23 (3H, s), 3.93 (2H, s),4.27 (2H, s), 5.39 (2H, s), 6.99 (1H, dd, J=5.1, 3.4), 7.14-7.24 (3H,m), 7.26-7.32 (2H, m), 7.43-7.58 (3H, m), 7.62-7.73 (2H, m), 12.39 (1H,s)

Example 54

6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-oxo-2-phenylethyl)pyrimidin-4(3H)-one

A mixture of6-butyl-3-(2-hydroxy-2-phenylethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.25 g), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.3 g) and methylene chloride (10 mL) was stirred at room temperaturefor 2 hr. A saturated aqueous sodium hydrogen carbonate solution andsodium thiosulfate were added to the reaction mixture, and the mixturewas stirred at room temperature for 2 hr and extracted with chloroform.The chloroform layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.2 g,78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.3), 1.22-1.39 (2H, m),1.39-1.58 (2H, m), 2.37 (3H, s), 2.51-2.56 (2H, m), 3.85 (2H, s), 5.65(2H, s), 7.21 (4H, s), 7.43-7.83 (7H, m), 8.02-8.15 (2H, m), 12.37 (1H,s)

Example 55

6-butyl-3-(2,2-dimethylpropyl)-2-(hydroxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of6-butyl-3-(2,2-dimethylpropyl)-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.5 g), boron tribromide (1.0 M dichloromethane solution, 2.9 mL) anddichloromethane (20 mL) was stirred at room temperature for 3 hr, 0.5 Maqueous sodium hydroxide solution (10 mL) was added, and the mixture wasfurther stirred for 1 hr. To the reaction mixture was added 1 Mhydrochloric acid and adjusted to pH 5. Ethyl acetate was added, and themixture was extracted. The ethyl acetate layer was washed with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.48 g, 98%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.3), 0.90 (9H, s), 1.21-1.36(2H, m), 1.41-1.53 (2H, m), 2.50-2.57 (2H, m), 3.87 (2H, s), 4.03 (2H,s), 4.50 (2H, d, J=5.3), 5.51 (1H, t, J=5.7), 7.15-7.28 (4H, m),7.44-7.60 (2H, m), 7.60-7.74 (2H, m), 12.37 (1H, s)

Example 566-butyl-3-(4-chlorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

56a)4′-{[4-butyl-1-(4-chlorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) wasstirred at room temperature for 10 min, 1-(bromomethyl)-4-chlorobenzene(0.69 g) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.84 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.31-1.46 (2H, m),1.51-1.65 (2H, m), 2.44 (3H, s), 2.56-2.65 (2H, m), 4.00 (2H, s), 5.25(2H, s), 7.14 (2H, d, J=8.3), 7.25-7.52 (8H, m), 7.58-7.66 (1H, m), 7.75(1H, d, J=7.3)

56b)6-butyl-3-(4-chlorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.81 g), sodium hydrogencarbonate (2.92 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-chlorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.84 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.42 g,45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.19-1.36 (2H, m),1.36-1.54 (2H, m), 2.38 (3H, s), 2.43-2.49 (2H, m), 3.90 (2H, s), 5.27(2H, s), 7.16-7.30 (6H, m), 7.37-7.47 (2H, m), 7.53 (2H, dd, J=15.6,7.7), 7.60-7.79 (2H, m), 12.39 (1H, s)

Example 576-butyl-2-methyl-3-(4-methylbenzyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

57a)4′-{[4-butyl-2-methyl-1-(4-methylbenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) wasstirred at room temperature for 10 min, 1-(bromomethyl)-4-methylbenzene(0.62 g) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.79 g, 61%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.30-1.46 (2H, m),1.49-1.65 (2H, m), 2.32 (3H, s), 2.45 (3H, s), 2.55-2.64 (2H, m), 4.01(2H, s), 5.26 (2H, s), 7.11 (4H, q, J=8.1), 7.34-7.52 (6H, m), 7.58-7.65(1H, m), 7.75 (1H, d, J=9.0)

57b)6-butyl-2-methyl-3-(4-methylbenzyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.79 g), sodium hydrogencarbonate (2.87 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(4-methylbenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.79 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.33 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.53 g,59%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.18-1.37 (2H, m),1.36-1.53 (2H, m), 2.27 (3H, s), 2.38 (3H, s), 2.44-2.49 (2H, m), 3.90(2H, s), 5.24 (2H, s), 7.06 (2H, d, J=8.1), 7.17 (2H, d, J=7.9),7.20-7.29 (4H, m), 7.46-7.61 (2H, m), 7.62-7.79 (2H, m), 12.39 (1H, s)

Example 586-butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

58a)4′-{[4-butyl-1-(4-methoxybenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) wasstirred at room temperature for 10 min,1-(chloromethyl)-4-methoxybenzene (0.46 mL) was added, and the mixturewas stirred at room temperature for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.83 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.31-1.45 (2H, m),1.49-1.66 (2H, m), 2.47 (3H, s), 2.54-2.64 (2H, m), 3.78 (3H, s), 4.01(2H, s), 5.23 (2H, s), 6.88 (2H, d, J=8.7), 7.15 (2H, d, J=8.7),7.34-7.52 (6H, m), 7.58-7.69 (1H, m), 7.72-7.79 (1H, m)

58b)6-butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.81 g), sodium hydrogencarbonate (2.92 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-methoxybenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.83 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.51 g,54%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.21-1.36 (2H, m),1.36-1.51 (2H, m), 2.39 (3H, s), 2.45-2.49 (2H, m), 3.73 (3H, s), 3.90(2H, s), 5.21 (2H, s), 6.92 (2H, d, J=8.7), 7.14 (2H, d, J=8.7),7.19-7.33 (4H, m), 7.47-7.61 (2H, m), 7.60-7.77 (2H, m), 12.39 (1H, s)

6-Butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(4-methoxybenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 596-butyl-3-(4-tert-butylbenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

59a)4′-{[4-butyl-1-(4-tert-butylbenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) wasstirred at room temperature for 10 min,1-(bromomethyl)-4-tert-butylbenzene (0.62 mL) was added, and the mixturewas stirred at room temperature for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.86 g, 61%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.29 (9H, s), 1.34-1.45(2H, m), 1.49-1.59 (2H, m), 2.47 (3H, s), 2.54-2.65 (2H, m), 4.01 (2H,s), 5.27 (2H, s), 7.13 (2H, d, J=8.3), 7.31-7.54 (8H, m), 7.55-7.67 (1H,m), 7.75 (1H, dd, J=7.7, 1.3)

59b)6-butyl-3-(4-tert-butylbenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.79 g), sodium hydrogencarbonate (2.87 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-tert-butylbenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.86 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.33 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.55 g,57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.22-1.37 (11H, m),1.39-1.54 (2H, m), 2.39 (3H, s), 2.45-2.49 (2H, m), 3.90 (2H, s), 5.24(2H, s), 7.10 (2H, d, J=8.5), 7.19-7.32 (4H, m), 7.38 (2H, d, J=8.3),7.47-7.61 (2H, m), 7.61-7.75 (2H, m), 12.39 (1H, s)

Example 606-butyl-2-methyl-3-[(5-methyl-1-benzothien-2-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

60a)4′-({4-butyl-2-methyl-1-[(5-methyl-1-benzothien-2-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), (5-methyl-1-benzothien-2-yl)methanol (0.75 g) andtetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.63 g,44%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.4), 1.29-1.43 (2H, m),1.48-1.60 (2H, m), 2.43 (3H, s), 2.54-2.64 (5H, m), 4.02 (2H, s), 5.45(2H, s), 7.10-7.19 (2H, m), 7.34-7.53 (7H, m), 7.56-7.67 (2H, m), 7.74(1H, dd, J=7.7, 0.9)

60b)6-butyl-2-methyl-3-[(5-methyl-1-benzothien-2-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.28 g), sodium hydrogencarbonate (2.07 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-1-[(5-methyl-1-benzothien-2-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.25 g,35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (3H, t, J=7.2), 1.16-1.34 (2H, m),1.35-1.53 (2H, m), 2.39 (3H, s), 2.43-2.49 (2H, m), 2.56 (3H, s), 3.91(2H, s), 5.49 (2H, s), 7.12-7.35 (5H, m), 7.38 (1H, s), 7.44-7.74 (5H,m), 7.79 (1H, d, J=8.1), 12.38 (1H, s)

Example 616-butyl-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

61a)4′-({4-butyl-1-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), (2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methanol (0.75 g)and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr.The reaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.67 g,46%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3), 1.31-1.42 (2H, m), 1.44(6H, s), 1.49-1.60 (2H, m), 2.48 (3H, s), 2.55-2.64 (2H, m), 3.01 (2H,s), 4.00 (2H, s), 5.23 (2H, s), 6.76 (1H, t, J=7.5), 6.92 (1H, d,J=7.3), 7.04 (1H, dd, J=7.2, 0.9), 7.32-7.52 (6H, m), 7.56-7.66 (1H, m),7.74 (1H, dd, J=7.7, 0.8)

61b)6-butyl-3-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.35 g), sodium hydrogencarbonate (2.17 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.67 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.16 g,21%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.2), 1.22-1.33 (2H, m),1.36-1.51 (8H, m), 2.39 (3H, s), 2.45-2.49 (2H, m), 3.01 (2H, s), 3.88(2H, s), 5.13 (2H, s), 6.67-6.81 (2H, m), 7.10 (1H, d, J=7.0), 7.18-7.27(4H, m), 7.46-7.59 (2H, m), 7.61-7.72 (2H, m), 12.39 (1H, br)

Example 626-butyl-3-[(6-ethylpyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

62a)4′-({4-butyl-1-[(6-ethylpyridin-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of (6-ethylpyridin-3-yl)methanol hydrochloride (0.74 g) andsaturated potassium carbonate (10 mL) was extracted with chloroform. Thechloroform layer was dried over anhydrous magnesium sulfate, and thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (50 mL),4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g) and tributylphosphine(1.56 mL) were added, and the mixture was stirred at room temperaturefor 16 hr. The reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.93 g,70%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t), 1.22-1.45 (7H, m), 2.49 (3H, s),2.57-2.65 (2H, m), 2.75-2.89 (2H, m), 3.99 (2H, s), 5.26 (2H, s), 7.15(1H, d, J=8.1), 7.32-7.53 (7H, m), 7.58-7.66 (1H, m), 7.74 (1H, dd,J=7.7, 0.8), 8.44 (1H, d, J=2.3)

62b)6-butyl-3-[(6-ethylpyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.04 g), sodium hydrogencarbonate (3.28 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[(6-ethylpyridin-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.93 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.38 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, andthe mixture was stirred at room temperature for 2 hr. Water was added tothe reaction mixture, and 1 M hydrochloric acid was added and adjustedto pH 5, and the mixture was extracted with ethyl acetate. The ethylacetate layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.38 g, 36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.15-1.36 (5H, m),1.37-1.55 (2H, m), 2.36-2.51 (5H, m), 2.72 (2H, q, J=7.5), 3.90 (2H, s),5.26 (2H, s), 7.17-7.35 (5H, m), 7.45-7.58 (3H, m), 7.62-7.75 (2H, m),8.40 (1H, d, J=1.9), 12.40 (1H, s)

Example 636-butyl-3-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

63a)4′-({4-butyl-1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), (2,4-dimethyl-1,3-thiazol-5-yl)methanol (0.6 g) andtetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (1.33 g, 99%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (3H, t, J=7.4), 1.31-1.74 (4H, m), 2.47(3H, s), 2.51-2.57 (5H, m), 2.59 (3H, s), 4.00 (2H, s), 5.26 (2H, s),7.33-7.51 (6H, m), 7.58-7.66 (1H, m), 7.74 (1H, dd, J=7.7, 0.9)

63b)6-butyl-3-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.9 g), sodium hydrogencarbonate (4.7 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.33 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.49 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.42 g,27%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.15-1.35 (2H, m),1.34-1.52 (2H, m), 2.39 (3H, s), 2.41-2.48 (2H, m), 2.49 (3H, s), 2.52(3H, s), 3.89 (2H, s), 5.29 (2H, s), 7.17-7.32 (4H, m), 7.43-7.61 (2H,m), 7.61-7.80 (2H, m), 12.39 (1H, s)

Example 643-(1,3-benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

64a)4′-{[1-(1,3-benzothiazol-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), 1,3-benzothiazol-2-ylmethanol (0.69 g) and tetrahydrofuran(50 mL) was stirred at room temperature for 4 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.63 g, 45%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3), 1.30-1.43 (2H, m),1.48-1.63 (2H, m), 2.52-2.66 (2H, m), 2.70 (3H, s), 4.02 (2H, s), 5.63(2H, s), 7.36-7.53 (8H, m), 7.57-7.66 (1H, m), 7.74 (1H, d, J=7.7), 7.87(1H, d, J=7.3), 8.01 (1H, d, J=8.1)

64b)3-(1,3-benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.31 g), sodium hydrogencarbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[1-(1,3-benzothiazol-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.2 g,28%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.22-1.36 (2H, m),1.38-1.52 (2H, m), 2.51-2.55 (2H, m), 2.58 (3H, s), 3.89 (2H, s), 5.66(2H, s), 7.17-7.29 (4H, m), 7.41-7.58 (4H, m), 7.62-7.72 (2H, m), 8.02(1H, d, J=8.7), 8.11 (1H, d, J=8.7), 12.38 (1H, s)

3-(1,3-Benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(1,3-benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   3-(1,3-benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   3-(1,3-benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   3-(1,3-benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   3-(1,3-benzothiazol-2-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 656-butyl-3-(4-fluorobenzyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

65a)4′-{[4-butyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-mercapto-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.3 g), iodomethane (0.54 mL), potassium hydroxide (0.44 g) andmethanol (20 mL) was stirred at room temperature for 3 hr. The obtainedcrystallized product was collected by filtration and washed with waterand diethyl ether to give the title compound as colorless crystals (1.98g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.4), 1.26-1.42 (2H, m),1.51-1.66 (2H, m), 2.52-2.64 (5H, m), 3.95 (2H, s), 7.37-7.50 (6H, m),7.57-7.65 (1H, m), 7.74 (1H, dd, J=7.7, 1.3), 12.56 (1H, br)

65b)4′-[(4-butyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-{[4-butyl-2-(methylthio)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.98 g), Raney-nickel (15 g) and 1-methoxy-2-(2-methoxyethoxy)ethane(25 mL) was stirred at 160° C. for 16 hr. The insoluble material wasfiltrated, and the filtrate was concentrated to give the title compoundas colorless crystals (1.09 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.19-1.35 (2H, m),1.35-1.56 (2H, m), 2.51-2.58 (2H, m), 3.89 (2H, s), 7.34 (2H, d, J=8.3),7.43-7.64 (4H, m), 7.71-7.82 (1H, m), 7.93 (1H, d, J=7.7), 8.06 (1H, s),12.42 (1H, br)

65c)4′-{[4-butyl-1-(4-fluorobenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), sodium hydride (0.07 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-(bromomethyl)-4-fluorobenzene(0.22 mL) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.54 g, 82%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.4), 1.29-1.42 (2H, m),1.51-1.63 (2H, m), 2.57-2.68 (2H, m), 3.99 (2H, s), 5.06 (2H, s),7.01-7.10 (2H, m), 7.30-7.50 (8H, m), 7.57-7.67 (1H, m), 7.74 (1H, dd,J=7.7, 0.9), 8.06 (1H, s)

65d)6-butyl-3-(4-fluorobenzyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.25 g), sodium hydrogencarbonate (2.02 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-fluorobenzyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.23 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.38 g,62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.4), 1.20-1.33 (2H, m),1.37-1.55 (2H, m), 2.51-2.56 (2H, m), 3.87 (2H, s), 5.09 (2H, s),7.14-7.27 (6H, m), 7.37-7.45 (2H, m), 7.46-7.59 (2H, m), 7.62-7.73 (2H,m), 8.55 (1H, s), 12.37 (1H, s)

Example 666-butyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

66a)4′-{[4-butyl-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), cesium carbonate (4.1 g),(3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (2.36 g) andN,N-dimethylacetamide (10 mL) was stirred at 130° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.63 g,27%).

¹H NMR (300 MHz, CDCl₃) δ 0.03-0.11 (6H, m), 0.86-0.99 (18H, m),1.32-1.46 (2H, m), 1.49-1.62 (2H, m), 2.50-2.65 (5H, m), 3.33 (2H, s),3.95 (2H, s), 4.13 (2H, br), 7.31-7.40 (2H, m), 7.40-7.52 (4H, m),7.57-7.67 (2H, m), 7.74 (2H, dd, J=7.7, 0.9)

66b)6-butyl-3-(3-hydroxy-2,2-dimethylpropyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.17 g), sodium hydrogencarbonate (1.88 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.63 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (20 mL),tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 3.7 mL) wasadded, and the mixture was stirred at 70° C. for 6 hr. The reactionmixture was extracted with 1 M hydrochloric acid and ethyl acetate, andthe ethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.24 g,48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.74-0.90 (9H, m), 1.19-1.35 (2H, m),1.36-1.53 (2H, m), 2.41-2.48 (2H, m), 2.54 (3H, s), 3.09 (2H, d, J=4.7),3.85 (2H, s), 3.97 (2H, s), 4.84 (1H, t, J=5.2), 7.12-7.27 (4H, m),7.43-7.58 (2H, m), 7.61-7.74 (2H, m), 12.37 (1H, s)

Example 676-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1-phenylethyl)pyrimidin-4(3H)-one

67a)4′-{[4-butyl-2-methyl-6-oxo-1-(1-phenylethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), cesium carbonate (2.73 g), (1-bromoethyl)benzene (1.15 mL) andN,N-dimethylacetamide (10 mL) was stirred at 130° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.24 g,19%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.30-1.43 (2H, m),1.48-1.63 (2H, m), 1.91 (3H, d, J=7.2), 2.27 (3H, s), 2.49-2.59 (2H, m),3.98 (2H, s), 6.51 (1H, br), 7.16-7.51 (11H, m), 7.58-7.67 (1H, m), 7.74(1H, dd, J=7.7, 0.9)

67b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1-phenylethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.87 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(1-phenylethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.24 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.1 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.07 g,26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.21-1.34 (2H, m),1.36-1.50 (2H, m), 1.86 (3H, d, J=7.0), 2.33-2.47 (5H, m), 3.81 (2H, s),6.09 (1H, br), 7.14-7.30 (7H, m), 7.32-7.39 (2H, m), 7.52 (2H, dd,J=17.6, 7.6), 7.62-7.72 (2H, m), 12.38 (1H, br)

6-Butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1-phenylethyl)pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1-phenylethyl)pyrimidin-4(3H)-one    sodium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1-phenylethyl)pyrimidin-4(3H)-one    potassium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1-phenylethyl)pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1-phenylethyl)pyrimidin-4(3H)-one    hydrochloride-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1-phenylethyl)pyrimidin-4(3H)-one    hydrobromide

Example 686-butyl-3-(2-chlorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

68a)4′-{[4-butyl-1-(2-chlorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.13 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-(bromomethyl)-2-chlorobenzene(0.44 mL) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.6 g, 45%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3), 1.31-1.48 (2H, m),1.54-1.69 (2H, m), 2.39 (3H, s), 2.59-2.70 (2H, m), 4.01 (2H, s), 5.39(2H, s), 6.74-6.82 (1H, m), 7.17-7.25 (2H, m), 7.36-7.51 (7H, m), 7.62(1H, t, J=7.6), 7.74 (1H, d, J=7.7)

68b)6-butyl-3-(2-chlorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.1 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2-chlorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.45 g,67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.2), 1.24-1.35 (2H, m),1.41-1.55 (2H, m), 2.36 (3H, s), 2.52-2.58 (2H, m), 3.89 (2H, s), 5.30(2H, s), 6.68-6.74 (1H, m), 7.17-7.28 (4H, m), 7.30-7.38 (2H, m),7.46-7.58 (3H, m), 7.62-7.71 (2H, m), 12.39 (1H, s)

Example 69

6-butyl-3-(2,6-dichlorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.13 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min,2-(bromomethyl)-1,3-dichlorobenzene (0.81 mL) was added, and the mixturewas stirred at room temperature for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and added to a mixture of hydroxylammoniumchloride (0.4 g), sodium hydrogen carbonate (0.65 g) and dimethylsulfoxide (10 mL) previously stirred at 40° C. for 30 min. The reactionmixture was stirred at 90° C. for 16 hr, and diluted with ethyl acetate.The mixture was washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (20 mL),N,N′-carbonyldiimidazole (0.075 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.064 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.047g, 3%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.4), 1.16-1.31 (2H, m),1.36-1.51 (2H, m), 2.41-2.49 (5H, m), 3.79 (2H, s), 5.46 (2H, s),7.10-7.20 (4H, m), 7.27-7.37 (1H, m), 7.41-7.58 (4H, m), 7.61-7.71 (2H,m), 12.39 (1H, br)

Example 706-butyl-2-methyl-3-(2-morpholin-4-ylethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

70a)4′-{[4-butyl-2-methyl-1-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), 2-morpholin-4-ylethanol (0.51 mL) and tetrahydrofuran (50 mL)was stirred at room temperature for 4 hr. The reaction mixture wasdiluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (1.34 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (3H, t, J=7.3), 1.31-1.49 (4H, m),2.44-2.50 (4H, m), 2.57 (3H, s), 2.65-2.75 (4H, m), 3.59-3.69 (4H, m),4.01 (2H, s), 4.50 (2H, t, J=5.7), 7.22-7.29 (2H, m), 7.38-7.50 (4H, m),7.59-7.67 (1H, m), 7.75 (1H, d, J=7.7)

70b)6-butyl-2-methyl-3-(2-morpholin-4-ylethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.9 g), sodium hydrogencarbonate (4.77 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(2-morpholin-4-ylethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.34 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.55 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.58 g, 39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.4), 1.19-1.37 (2H, m),1.41-1.54 (2H, m), 2.37-2.48 (7H, m), 2.58-2.71 (4H, m), 3.44-3.53 (4H,m), 3.95 (2H, s), 4.45 (2H, t, J=5.6), 7.18-7.26 (4H, m), 7.44-7.61 (2H,m), 7.58-7.74 (2H, m)

Example 716-butyl-3-[(6-methoxypyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

71a)4′-({4-butyl-1-[(6-methoxypyridin-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), (6-methoxypyridin-3-yl)methanol (0.58 g) and tetrahydrofuran(50 mL) was stirred at room temperature for 4 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (1.09 g, 81%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.2), 1.31-1.44 (2H, m),1.49-1.63 (2H, m), 2.50 (3H, s), 2.55-2.65 (2H, m), 3.91 (3H, s), 3.99(2H, s), 5.19 (2H, s), 6.68-6.78 (1H, m), 7.32-7.65 (8H, m), 7.74 (1H,d, J=7.7), 8.08 (1H, s)

71b)6-butyl-3-[(6-methoxypyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.37 g), sodium hydrogencarbonate (3.83 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[(6-methoxypyridin-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.09 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.44 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.38 g, 32%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.19-1.33 (2H, m),1.36-1.52 (2H, m), 2.42-2.47 (5H, m), 3.83 (3H, s), 3.89 (2H, s), 5.21(2H, s), 6.82 (1H, d, J=8.7), 7.17-7.30 (4H, m), 7.47-7.59 (3H, m),7.62-7.74 (2H, m), 8.12 (1H, s), 12.39 (1H, s)

6-Butyl-3-[(6-methoxypyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-[(6-methoxypyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-[(6-methoxypyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-[(6-methoxypyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-[(6-methoxypyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-[(6-methoxypyridin-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 726-butyl-3-[(5-chloro-1-benzothien-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

72a)4′-({4-butyl-1-[(5-chloro-1-benzothien-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), (5-chloro-1-benzothien-3-yl)methanol (0.83 g) andtetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.82 g,55%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.4), 1.32-1.47 (2H, m),1.52-1.67 (2H, m), 2.48 (3H, s), 2.60-2.68 (2H, m), 4.02 (2H, s), 5.45(2H, s), 7.05 (1H, s), 7.32-7.51 (7H, m), 7.59-7.67 (1H, m), 7.72-7.84(3H, m)

72b)6-butyl-3-[(5-chloro-1-benzothien-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.62 g), sodium hydrogencarbonate (2.6 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[(5-chloro-1-benzothien-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.82 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.30 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.58 g,62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.22-1.35 (2H, m),1.41-1.52 (2H, m), 2.41-2.51 (5H, m), 3.92 (2H, s), 5.50 (2H, s), 7.25(4H, q, J=8.2), 7.42-7.60 (4H, m), 7.63-7.74 (2H, m), 8.03-8.15 (2H, m),12.38 (1H, br)

Example 736-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(2-phenyl-1,3-thiazol-5-yl)methyl]pyrimidin-4(3H)-one

73a)4′-({4-butyl-2-methyl-6-oxo-1-[(2-phenyl-1,3-thiazol-5-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), (2-phenyl-1,3-thiazol-5-yl)methanol (0.8 g) andtetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.93 g, 63%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3), 1.29-1.46 (2H, m),1.50-1.62 (2H, m), 2.55-2.63 (2H, m), 2.82 (3H, s), 3.97 (2H, s), 5.37(2H, s), 7.24-7.50 (10H, m), 7.57-7.65 (1H, m), 7.74 (1H, dd, J=7.7,0.9), 7.88-7.96 (2H, m)

73b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(2-phenyl-1,3-thiazol-5-yl)methyl]pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.83 g), sodium hydrogencarbonate (2.94 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-6-oxo-1-[(2-phenyl-1,3-thiazol-5-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.93 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.6 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.20-1.35 (2H, m),1.38-1.53 (2H, m), 2.44-2.49 (2H, m), 2.66 (3H, s), 3.86 (2H, s), 5.35(2H, s), 7.14-7.25 (4H, m), 7.42-7.61 (6H, m), 7.59-7.69 (2H, m),7.84-7.91 (2H, m), 12.36 (1H, s)

Example 746-butyl-3-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

74a)4′-({4-butyl-1-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), (1,5-dimethyl-1H-pyrazol-3-yl)methanol (0.53 g) andtetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.80 g, 61%).

¹H NMR (300 MHz, CDCl₃) δ 0.87-0.95 (3H, m), 1.33-1.48 (4H, m), 2.19(3H, s), 2.54 (3H, s), 2.56-2.66 (2H, m), 3.82 (3H, s), 3.97 (2H, s),5.22 (2H, s), 5.74 (1H, s), 7.30-7.50 (6H, m), 7.56-7.66 (1H, m), 7.74(1H, d, J=7.7)

74b)6-butyl-3-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.79 g), sodium hydrogencarbonate (2.89 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.8 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.25 g, 27%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.2), 1.22-1.49 (4H, m), 2.05(3H, s), 2.42-2.48 (5H, m), 3.77 (3H, s), 3.87 (2H, s), 5.23 (2H, s),5.61 (1H, s), 7.19-7.25 (4H, m), 7.52 (2H, dd, J=17.8, 7.2), 7.62-7.73(2H, m), 12.43 (1H, br)

Example 756-butyl-2-methyl-3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

75a)4′-{[1-(1H-benzimidazol-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), cesium carbonate (1.82 g), tert-butyl2-(chloromethyl)-1H-benzimidazole-1-carboxylate (1.12 g), potassiumiodide (0.046 g) and N,N-dimethylacetamide (10 mL) was stirred at 130°C. for 3 days. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.24 g,18%).

¹H NMR (300 MHz, CDCl₃) δ 0.88 (3H, t, J=7.3), 1.26-1.41 (2H, m),1.47-1.61 (2H, m), 2.52-2.64 (2H, m), 2.83 (3H, s), 4.02 (2H, s), 5.40(2H, s), 7.20-7.30 (3H, m), 7.34 (1H, d, J=8.3), 7.38-7.52 (5H, m),7.57-7.68 (1H, m), 7.71-7.80 (2H, m)

75b)4′-({4-butyl-2-methyl-1-[(1-methyl-1H-benzimidazol-2-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[1-(1H-benzimidazol-2-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.24 g), iodomethane (0.036 mL), potassium carbonate (0.14 g) andN,N-dimethylformamide (5 mL) was stirred at room temperature for 3 hr.The reaction mixture was diluted with ethyl acetate, washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.25 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3), 1.31-1.44 (2H, m),1.51-1.65 (2H, m), 2.54-2.65 (2H, m), 2.85 (3H, s), 3.87 (3H, s), 3.95(2H, s), 5.51 (2H, s), 7.20-7.49 (9H, m), 7.57-7.66 (1H, m), 7.68-7.76(2H, m)

75c)6-butyl-2-methyl-3-[(1-methyl-1H-benzimidazol-2-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.51 g), sodium hydrogencarbonate (0.82 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-1-[(1-methyl-1H-benzimidazol-2-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.25 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.096 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.08 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.18 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.25-1.39 (2H, m),1.41-1.56 (2H, m), 2.52-2.56 (2H, m), 2.59 (3H, s), 3.84 (2H, s), 3.90(3H, s), 5.51 (2H, s), 7.12-7.29 (6H, m), 7.43-7.59 (4H, m), 7.61-7.71(2H, m), 12.37 (1H, br)

Example 76

2-methyl-3-(4-methylbenzyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(4 g), sodium hydride (0.7 g) and N,N-dimethylformamide (40 mL) wasstirred at room temperature for 10 min, 1-(bromomethyl)-4-methylbenzene(2.57 g) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue obtained by silica gelcolumn chromatography was dissolved in dimethyl sulfoxide (15 mL), andadded to a mixture of hydroxylammonium chloride (7.78 g), sodiumhydrogen carbonate (12.5 g) and dimethyl sulfoxide (30 mL) previouslystirred at 40° C. for 30 min. The reaction mixture was stirred at 90° C.for 16 hr, and diluted with ethyl acetate. The mixture was washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas dissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (1.45g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (2.42 g,64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.4), 1.41-1.60 (2H, m), 2.27(3H, s), 2.38 (3H, s), 2.44-2.48 (2H, m), 3.91 (2H, s), 5.24 (2H, s),7.06 (2H, d, J=8.1), 7.17 (2H, d, J=7.9), 7.20-7.30 (4H, m), 7.53 (2H,dd, J=13.4, 7.2), 7.59-7.75 (2H, m), 12.38 (1H, s)

Example 776-butyl-2-methyl-3-[(5-methylpyridin-2-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

77a)4′-({4-butyl-2-methyl-1-[(5-methylpyridin-2-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), (5-methylpyridin-2-yl)methanol (0.5 g) and tetrahydrofuran(50 mL) was stirred at room temperature for 4 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.59 g, 47%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.4), 1.29-1.46 (2H, m),1.49-1.64 (2H, m), 2.31 (3H, s), 2.55-2.68 (5H, m), 3.98 (2H, s), 5.33(2H, s), 7.16 (1H, d, J=8.0), 7.33-7.53 (7H, m), 7.57-7.67 (1H, m), 7.74(1H, d, J=8.0), 8.35 (1H, d, J=1.9)

77b)6-butyl-2-methyl-3-[(5-methylpyridin-2-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-1-[(5-methylpyridin-2-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.59 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.42 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.3), 1.23-1.37 (2H, m),1.39-1.53 (2H, m), 2.27 (3H, s), 2.44-2.51 (5H, m), 3.84 (2H, s), 5.29(2H, s), 7.15-7.26 (5H, m), 7.45-7.74 (5H, m), 8.32 (1H, d, J=0.8),12.38 (1H, s)

Example 786-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyrazin-2-ylmethyl)pyrimidin-4(3H)-one

78a)4′-{[4-butyl-2-methyl-6-oxo-1-(pyrazin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.56 mL), pyrazin-2-ylmethanol (0.46 g) and tetrahydrofuran (50 mL) wasstirred at room temperature for 4 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.87 g,69%).

¹H NMR (300 MHz, CDCl₃) δ 0.87-0.98 (3H, m), 1.35-1.50 (4H, m),2.55-2.68 (5H, m), 3.96 (2H, s), 5.37 (2H, s), 7.29-7.53 (6H, m),7.56-7.65 (1H, m), 7.74 (1H, d, J=7.6), 8.53 (2H, s), 8.71 (1H, s)

78b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyrazin-2-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.1 g), sodium hydrogencarbonate (3.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(pyrazin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.87 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.38 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.4 g, 38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.0), 1.22-1.36 (2H, m),1.38-1.53 (2H, m), 2.42-2.58 (5H, m), 3.83 (2H, s), 5.40 (2H, s),7.17-7.23 (4H, m), 7.43-7.59 (2H, m), 7.61-7.71 (2H, m), 8.56 (2H, s),8.76 (1H, s), 12.02 (1H, br)

Example 792-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one

79a)4′-{[2-methyl-6-oxo-4-propyl-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(7 g), 1,1′-(azodicarbonyl)dipiperidine (9.9 g), tributylphosphine (12.2mL), pyridin-2-ylmethanol (2.8 mL) and tetrahydrofuran (350 mL) wasstirred at room temperature for 4 hr. The reaction mixture wasconcentrated, and the residue was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (2.6 g, 31%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (3H, t, J=7.3), 1.56-1.72 (2H, m),2.54-2.64 (5H, m), 3.99 (2H, s), 5.38 (2H, s), 7.12-7.27 (2H, m),7.32-7.52 (6H, m), 7.56-7.71 (2H, m), 7.74 (1H, dd, J=7.7, 1.3), 8.54(1H, dd, J=4.0, 0.9)

79b)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (6.23 g), sodium hydrogencarbonate (10.1 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-6-oxo-4-propyl-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (1.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.99 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (2.07 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.3), 1.42-1.60 (2H, m),2.43-2.49 (5H, m), 3.85 (2H, s), 5.34 (2H, s), 7.16-7.25 (4H, m),7.27-7.38 (2H, m), 7.46-7.57 (2H, m), 7.62-7.73 (2H, m), 7.76-7.85 (1H,m), 8.46-8.51 (1H, m), 12.37 (1H, s)

Example 806-butyl-3-(3-fluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

80a)4′-{[4-butyl-1-(3-fluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-(bromomethyl)-3-fluorobenzene(0.41 g) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.82 g, 63%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.2), 1.30-1.46 (2H, m),1.52-1.66 (2H, m), 2.44 (3H, s), 2.54-2.67 (2H, m), 4.01 (2H, s), 5.28(2H, s), 6.85-7.02 (3H, m), 7.24-7.51 (7H, m), 7.62 (1H, t, J=7.8), 7.74(1H, d, J=8.0)

80b)6-butyl-3-(3-fluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.83 g), sodium hydrogencarbonate (2.96 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-fluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.86 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.64 g,69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.22-1.35 (2H, m),1.38-1.53 (2H, m), 2.39 (3H, s), 2.46-2.53 (2H, m), 3.91 (2H, s), 5.29(2H, s), 6.94-7.07 (2H, m), 7.08-7.18 (1H, m), 7.19-7.29 (4H, m),7.36-7.46 (1H, m), 7.46-7.58 (2H, m), 7.62-7.72 (2H, m), 12.39 (1H, s)

Example 812-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one

81a)4′-{[2-methyl-6-oxo-4-propyl-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 2-(bromomethyl)tetrahydro-2H-pyran (0.45 mL), potassium carbonate(0.60 g) and N,N-dimethylformamide (10 mL) was stirred at 90° C. for 3hr. The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.64 g, 48%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (3H, t, J=7.4), 1.27-1.37 (1H, m),1.43-1.68 (5H, m), 1.69-1.79 (1H, m), 1.80-1.90 (1H, m), 2.53-2.64 (5H,m), 3.24-3.36 (1H, m), 3.62-3.75 (2H, m), 3.86-4.04 (3H, m), 4.19-4.31(1H, m), 7.32-7.51 (6H, m), 7.57-7.65 (1H, m), 7.74 (1H, d, J=7.6)

81b)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.47 g), sodium hydrogencarbonate (2.37 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-6-oxo-4-propyl-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.64 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.48 g,68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.3), 1.22-1.35 (1H, m),1.37-1.55 (5H, m), 1.63 (1H, d, J=13.9), 1.78 (1H, br), 2.40-2.55 (5H,m), 3.17-3.28 (1H, m), 3.56 (1H, t, J=8.3), 3.74-3.92 (4H, m), 4.04-4.15(1H, m), 7.16-7.28 (4H, m), 7.44-7.57 (2H, m), 7.61-7.73 (2H, m), 12.36(1H, s)

2-Methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    sodium salt-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    potassium salt-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    0.5 calcium salt-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    hydrochloride-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    hydrobromide

Example 826-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1,3-thiazol-2-ylmethyl)pyrimidin-4(3H)-one

82a)4′-{[4-butyl-2-methyl-6-oxo-1-(1,3-thiazol-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine(1.74 mL), 1,3-thiazol-2-ylmethanol (0.48 g) and tetrahydrofuran (50 mL)was stirred at room temperature for 4 hr. The reaction mixture wasconcentrated. The residue was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.96 g, 75%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (3H, t, J=7.2), 1.32-1.48 (4H, m),2.53-2.63 (2H, m), 2.70 (3H, s), 3.99 (2H, s), 5.52 (2H, s), 7.31-7.50(7H, m), 7.57-7.67 (1H, m), 7.70-7.78 (2H, m)

82b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1,3-thiazol-2-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.2 g), sodium hydrogencarbonate (3.5 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(1,3-thiazol-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.96 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.41 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.47 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.2), 1.21-1.35 (2H, m),1.36-1.51 (2H, m), 2.43-2.49 (2H, m), 2.58 (3H, s), 3.87 (2H, s), 5.52(2H, s), 7.16-7.28 (4H, m), 7.46-7.58 (2H, m), 7.61-7.73 (3H, m), 7.77(1H, d, J=3.2), 12.38 (1H, s)

Example 83

2-methyl-3-[4-(methylsulfonyl)benzyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.48 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min,1-(bromomethyl)-4-(methylsulfonyl)benzene (0.87 g) was added, and themixture was stirred at room temperature for 16 hr. The reaction mixturewas diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue obtained by silica gel column chromatography wasdissolved in dimethyl sulfoxide (5 mL), and added to a mixture ofhydroxylammonium chloride (0.51 g), sodium hydrogen carbonate (0.82 g)and dimethyl sulfoxide (10 mL) previously stirred at 40° C. for 30 min.The reaction mixture was stirred at 90° C. for 16 hr, and diluted withethyl acetate. The mixture was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was dissolved intetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.096 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.081 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.19 g,11%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.3), 1.46-1.61 (2H, m), 2.48(3H, s), 2.59-2.69 (2H, m), 3.19 (3H, s), 4.03 (2H, s), 5.52 (2H, s),7.13-7.26 (4H, m), 7.46-7.60 (4H, m), 7.62-7.72 (2H, m), 7.88 (2H, d,J=8.5), 12.38 (1H, s)

Example 84 methyl2-[(2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl)methyl]benzoate

84a) methyl2-({5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}methyl)benzoate

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2 g), sodium hydride (0.28 g) and N,N-dimethylformamide (20 mL) wasstirred at room temperature for 10 min, methyl 2-(bromomethyl)benzoate(1.6 g) was added, and the mixture was stirred at room temperature for16 hr. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (1.15 g, 40%).

¹H NMR (300 MHz, CDCl₃) δ 0.99 (3H, t, J=7.3), 1.60-1.77 (2H, m), 2.39(3H, s), 2.58-2.68 (2H, m), 3.93 (3H, s), 4.01 (2H, s), 5.76 (2H, s),6.78 (1H, d, J=7.7), 7.30-7.51 (8H, m), 7.57-7.67 (1H, m), 7.74 (1H, dd,J=7.7, 0.9), 8.07 (1H, dd, J=7.8, 1.4)

84b) methyl2-[(2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl)methyl]benzoate

A mixture of hydroxylammonium chloride (2.44 g), sodium hydrogencarbonate (3.93 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C.for 30 min, methyl2-({5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}methyl)benzoate(1.15 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (0.45 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.48 g,37%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87 (3H, t, J=7.4), 1.46-1.61 (2H, m), 2.32(3H, s), 2.51-2.56 (2H, m), 3.90 (5H, s), 5.59 (2H, s), 6.70 (1H, d,J=7.3), 7.19-7.28 (4H, m), 7.39-7.72 (6H, m), 8.00 (1H, dd, J=7.7, 1.3),12.38 (1H, s)

Example 856-butyl-2-(hydroxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one

85a)4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1 g), cesium carbonate (2.1 g), 2-(bromomethyl)pyridine hydrobromide(0.81 g) and N,N-dimethylformamide (10 mL) was stirred at 50° C. for 4hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.62 g, 50%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.30-1.45 (2H, m),1.55-1.67 (2H, m), 2.61-2.71 (2H, m), 3.98 (2H, s), 4.75 (2H, s), 5.09(1H, br.), 5.21 (2H, s), 7.18-7.25 (1H, m), 7.30-7.35 (2H, m), 7.37-7.50(5H, m), 7.57-7.78 (3H, m), 8.49-8.53 (1H, m)

85b)6-butyl-2-(hydroxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyridin-2-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.39 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1-(pyridin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.62 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.26 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.18 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.3), 1.21-1.39 (2H, m),1.41-1.59 (2H, m), 2.51-2.61 (2H, m), 3.86 (2H, s), 4.48 (2H, d, J=5.7),5.41 (2H, s), 5.63 (1H, t, J=5.7), 7.21 (4H, s), 7.24-7.41 (2H, m), 7.52(2H, dd, J=18.2, 7.6), 7.64 (2H, d, J=7.0), 7.74-7.85 (1H, m), 8.46 (1H,s), 12.38 (1H, s)

Example 863-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

86a)4′-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a mixture of tetrahydro-4H-pyran-4-one (0.73 g), diiodomethane (0.7mL) and tetrahydrofuran (20 mL) was added methyllithium (2.1 M diethylether solution, 6.95 mL) at 0° C. The reaction mixture was stirred atroom temperature for 4 hr, and extracted with saturated aqueous ammoniumchloride solution and diethyl ether. The diethyl ether layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The obtained oil wasdissolved in N,N-dimethylformamide (15 mL),4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g) and potassium carbonate (0.8 g) were added, and the mixture wasstirred at 90° C. for 24 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.7 g, 53%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (3H, t, J=7.4), 1.48-1.81 (6H, m),2.55-2.63 (5H, m), 3.80 (4H, d, J=7.7), 3.97 (2H, s), 4.16 (2H, s), 4.71(1H, s), 7.25-7.50 (5H, m), 7.62 (1H, t, J=7.6), 7.74 (1H, d, J=7.5),8.02 (1H, s)

86b)3-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.57 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({1-[(4-hydroxytetrahydro-2H-pyran-4-yl)methyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.7 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.26 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.14 g,18%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.2), 1.13-1.73 (6H, m), 2.43(2H, t, J=7.6), 2.61 (3H, s), 3.49-3.67 (4H, m), 3.85 (2H, s), 3.97-4.11(2H, m), 4.96 (1H, s), 7.14-7.29 (4H, m), 7.52 (2H, dd, J=18.1, 7.5),7.60-7.72 (2H, m), 12.37 (1H, s)

Example 872-methyl-3-[(1-methyl-1H-indazol-3-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

87a)4′-({2-methyl-1-[(1-methyl-1H-indazol-3-yl)methyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 1,1′-(azodicarbonyl)dipiperidine (1.47 g), tributylphosphine(1.81 mL), (1-methyl-1H-indazol-3-yl)methanol (0.51 g) andtetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. Thereaction mixture was concentrated. The residue was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.67 g,47%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.4), 1.52-1.65 (2H, m),2.48-2.58 (2H, m), 2.72 (3H, s), 4.03 (5H, s), 5.64 (2H, s), 7.01-7.12(1H, m), 7.30-7.53 (8H, m), 7.58-7.67 (1H, m), 7.75 (1H, d, J=8.0), 7.86(1H, d, J=8.0)

87b)2-methyl-3-[(1-methyl-1H-indazol-3-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.43 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({2-methyl-1-[(1-methyl-1H-indazol-3-yl)methyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.67 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.38 g, 51%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.4), 1.40-1.56 (2H, m),2.40-2.48 (2H, m), 2.62 (3H, s), 3.89 (2H, s), 4.00 (3H, s), 5.58 (2H,s), 7.10 (1H, t, J=7.4), 7.22 (4H, q, J=8.2), 7.40 (1H, t, J=8.0),7.47-7.72 (5H, m), 7.79 (1H, d, J=8.3), 11.96 (1H, br)

Example 883-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

88a) ethyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate

To a suspension of sodium hydride (60% in oil, 19.1 g) intetrahydrofuran (500 ml) was added a solution of ethyl 3-oxohexanoate(116 g) in tetrahydrofuran (500 ml) dropwise at room temperature. Afterbeing stirred at room temperature for 30 min,4′-(bromomethyl)-biphenyl-2-carbonitrile (100 g) was added to themixture and the mixture was stirred at room temperature for 15 hr. Ethylacetate and saturated aqueous ammonium chloride solution were added tothe mixture. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers weresuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound as a pale yellow oil (129 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.86 (t, J=7.4 Hz, 3H), 1.22 (t, J=7.2 Hz,3H), 1.48-1.66 (m, 2H), 2.30-2.44 (m, 1H), 3.13-3.30 (m, 2H), 3.83 (t,J=7.5 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 7.28-7.79 (m, 8H)

88b)4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a suspension of acetamidine hydrochloride (70 g) in methanol (500 ml)was added sodium methoxide (28% in methanol, 214 g) dropwise, followedby addition of a solution of ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (129 g) in methanol(500 ml) at room temperature. After being stirred at room temperaturefor 15 hr, ethyl acetate and saturated aqueous ammonium chloridesolution were added. The layers were separated and the aqueous layer wasextracted with ethyl acetate. The combined organic layers weresuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingsolid was collected and washed with diisopropyl ether to give the titlecompound as a white solid (104 g, 82%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (t, J=7.3 Hz, 3H), 1.46-1.81 (m, 2H),2.40 (s, 3H), 2.51-2.72 (m, 2H), 3.97 (s, 2H), 7.33-7.79 (m, 8H), 13.02(s, 1H)

88c)4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.0 g), (4-isopropoxyphenyl)boronic acid (2.0 g), triethylamine (4.0mL), pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylenechloride (30 mL) was added copper(II) acetate (2.0 g), and the mixturewas stirred at room temperature for 2 days. The reaction mixture wasdiluted with ethyl acetate. The insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.88 g, 68%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.36 (d, J=6.1, 6H),1.54-1.82 (m, 2H), 2.18 (s, 3H), 2.47-2.79 (m, 2H), 3.97 (s, 2H),4.41-4.81 (m, 1H), 6.72-7.81 (m, 12H)

88d)3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (3.5 g), sodium hydrogencarbonate (5.0 g) and dimethyl sulfoxide (25 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.88 g) was added, and the mixture was stirred at 90° C. for 15 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (25 mL), N,N′-carbonyldiimidazole (0.97g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.54 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.2, 3H), 1.30 (d, J=6.1, 6H),1.42-1.66 (m, 2H), 2.07 (s, 3H), 2.45-2.56 (m, 2H), 3.86 (s, 2H),4.55-4.78 (m, 1H), 6.98-7.73 (m, 12H), 12.39 (s, 1H)

88e) Crystalline3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a suspension of hydroxylammonium chloride (186 g) in dimethylsulfoxide (1340 mL) was added sodium hydrogen carbonate (280 g) at 50°C. and stirred for 30 min, and then4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(160 g) was added to the mixture. After being stirred at 90° C. for 18hr, the mixture was allowed to cool to room temperature and the mixturewas poured into iced water. The mixture was stirred for 30 min and theprecipitate was collected. The solid was washed with water and dried invacuo at 80° C. The solid was dissolved in tetrahydrofuran (1300 mL),N,N′-carbonyldiimidazole (65 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (60 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (152 g, 85%).

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):4.64, 5.46, 8.40, 11.10, 12.60, 13.10, 14.14, 14.36, 14.60, 15.58,15.86, 16.24, 16.86, 17.52, 19.26, 19.72, 20.00, 20.40, 20.80, 21.12,21.70.

Anal calcd for C₃₂H₃₂N₄O₄: C, 71.62; H, 6.02; N, 10.44.

Found C, 71.63; H, 6.03; N, 10.37.

Example 89

3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onehydrochloride

3-(4-Isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.50 g) was dissolved in ethyl acetate (3 mL), and 4 M hydrochloricacid-ethyl acetate solution (0.28 mL) was added. Diisopropyl ether wasfurther added and the precipitated solid was collected by filtration togive the title compound (0.40 g, 75%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.2), 1.30 (6H, d, J=6.0),1.49-1.65 (2H, m), 2.27 (3H, s), 2.65 (2H, t, J=7.7), 3.91 (2H, s),4.63-4.74 (1H, m), 7.04-7.11 (2H, m), 7.20-7.37 (6H, m), 7.48-7.59 (2H,m), 7.63-7.73 (2H, m), 12.43 (1H, s)

Example 90

3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onehydrobromide

3-(4-Isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.50 g) was dissolved in ethyl acetate (10 mL), and 10% hydrogenbromide-ethanol solution (0.75 mL) was added. After allowing to standovernight at room temperature, the precipitated solid was collected byfiltration to give the title compound (0.41 g, 71%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.1), 1.30 (6H, d, J=6.0),1.47-1.62 (2H, m), 2.22 (3H, s), 2.62 (2H, t, J=7.5), 3.91 (2H, s),4.59-4.75 (1H, m), 7.07 (2H, d, J=9.0), 7.20-7.36 (6H, m), 7.46-7.60(2H, m), 7.62-7.74 (2H, m), 12.41 (1H, s)

Example 91

91a)3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(1.42 g) in ethanol (10.0 mL) was added 8 M aqueous potassium hydroxidesolution (0.33 mL), and the mixture was stirred at room temperature for1 hr. The reaction mixture was concentrated under reduced pressure, andthe residue was triturated with diisopropyl ether to give the titlecompound (1.45 g, 95%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.30 (d, J=6.1, 6H),1.51-1.66 (m, 2H), 2.05 (s, 3H), 2.51-2.57 (m, 2H), 3.81 (s, 2H),4.59-4.75 (m, 1H), 6.97-7.49 (m, 12H)

91b) Crystalline3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a suspension of3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(200 g), ethanol (200 mL), and diisopropyl ether (400 mL) was addedpotassium 2-ethyl hexanoate and the mixture was stirred at 60° C. for 1hr. To the mixture was added diisopropyl ether (1000 mL) dropwise. Themixture was stirred at reflux temperature for 24 hr, followed by beingcooled to room temperature. The obtained precipitate was collected,washed with diisopropyl ether, and dried under reduced pressure at 60°C. for 1 hr to give the title compound (120 g, 56%) as colorlesscrystals.

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.30 (d, J=6.1, 6H),1.46-1.69 (m, 2H), 2.06 (s, 3H), 2.47-2.61 (m, 2H), 3.81 (s, 2H),4.53-4.78 (m, 1H), 6.90-7.60 (m, 12H)

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):4.46, 6.32, 12.66, 12.84, 13.46, 13.74, 16.82, 17.08, 17.82, 17.98,18.38, 19.70, 20.34, 21.80, 22.18, 22.80, 24.08, 25.40, 26.70.

Anal calcd for C₃₂H₃₁N₄O₄K+0.5H₂O: C, 65.84; H, 5.53; N, 9.60.

Found C, 65.67; H, 5.54; N, 9.45.

Example 92

3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onesodium salt

To a solution of3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(1.07 g) in ethanol (1.0 mL) was added 8 M aqueous sodium hydroxidesolution (0.25 mL), and the mixture was stirred at room temperature for1 hr. The reaction mixture was concentrated under reduced pressure, andthe residue was triturated with diisopropyl ether to give the titlecompound (1.13 g, 100%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.29 (s, 3H), 1.31 (s,3H), 1.49-1.68 (m, 2H), 2.05 (s, 3H), 2.51-2.57 (m, 2H), 3.81 (s, 2H),4.58-4.74 (m, 1H), 6.95-7.52 (m, 12H)

Example 93

3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one0.5 calcium salt

To a solution of3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onesodium salt (0.56 g) in water (2.0 mL) was added calcium chloride (0.056g), and the mixture was stirred at room temperature for 1 hr. Theresulting solid was collected by filtration to give the title compound(0.40 g, 71%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.2, 3H), 1.29 (s, 3H), 1.31 (s,3H), 1.47-1.68 (m, 2H), 2.06 (s, 3H), 2.51-2.61 (m, 2H), 3.82 (s, 2H),4.60-4.75 (m, 1H), 6.96-7.56 (m, 12H)

Example 94

6-butyl-3-[2-(4-methoxyphenyl)ethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min,1-(2-bromoethyl)-4-methoxybenzene (0.95 g) was added, and the mixturewas stirred at 150° C. for 16 hr. The reaction mixture was diluted withethyl acetate, washed with 5% aqueous potassium hydrogen sulfatesolution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL), and added to a mixture of hydroxylammoniumchloride (0.41 g), sodium hydrogen carbonate (0.59 g) and dimethylsulfoxide (20 mL) previously stirred at 40° C. for 30 min. The reactionmixture was stirred at 90° C. for 16 hr, diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (20 mL),N,N′-carbonyldiimidazole (0.11 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.24 g,17%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.25 (2H, tt, J=14.5,7.2), 1.36-1.47 (2H, m), 2.37 (3H, s), 2.82-2.92 (2H, m), 3.27-3.45 (2H,m), 3.67-3.75 (3H, m), 3.88 (2H, s), 4.04-4.14 (2H, m), 6.84-6.89 (2H,m), 7.11-7.17 (2H, m), 7.20-7.26 (4H, m), 7.48-7.57 (2H, m), 7.63-7.71(2H, m), 11.72-12.92 (1H, br)

6-Butyl-3-[2-(4-methoxyphenyl)ethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-[2-(4-methoxyphenyl)ethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-[2-(4-methoxyphenyl)ethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-[2-(4-methoxyphenyl)ethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-[2-(4-methoxyphenyl)ethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-[2-(4-methoxyphenyl)ethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 95

6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-phenylpropyl)pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, (2-bromo-1-methylethyl)benzene(1.1 g) was added, and the mixture was stirred at 150° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by silica gel columnchromatography was dissolved in dimethyl sulfoxide (5 mL), and added toa mixture of hydroxylammonium chloride (0.28 g), sodium hydrogencarbonate (0.40 g) and dimethyl sulfoxide (20 mL) previously stirred at40° C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,and diluted with ethyl acetate. The mixture was washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.078 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.066 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.12 g,9%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.2), 1.20-1.30 (5H, m),1.33-1.45 (2H, m), 2.16 (3H, s), 2.36-2.48 (2H, m), 3.83-3.91 (4H, m),4.22 (1H, dd, J=13.5, 6.9), 7.16-7.30 (9H, m), 7.46-7.58 (2H, m),7.62-7.72 (2H, m), 11.98-12.74 (1H, m)

Example 96

6-butyl-2-methyl-3-[2-(1-naphthyl)ethyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-(2-bromoethyl)naphthalene (1.0g) was added, and the mixture was stirred at 150° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by silica gel columnchromatography was dissolved in dimethyl sulfoxide (5 mL), and added toa mixture of hydroxylammonium chloride (0.64 g), sodium hydrogencarbonate (0.92 g) and dimethyl sulfoxide (20 mL) previously stirred at40° C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,and diluted with ethyl acetate. The mixture was washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.18 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.33 g,22%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79-0.86 (3H, m), 1.17-1.31 (2H, m),1.35-1.46 (2H, m), 2.34 (3H, s), 2.40-2.48 (2H, m), 3.38-3.50 (2H, m),3.88-3.95 (2H, m), 4.18-4.29 (2H, m), 7.21-7.30 (4H, m), 7.42-7.46 (2H,m), 7.48-7.58 (4H, m), 7.63-7.71 (2H, m), 7.82-7.96 (2H, m), 8.27-8.33(1H, m), 12.39 (1H, d, J=2.8)

Example 97

6-butyl-3-[2-(3-fluorophenyl)ethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-(2-bromoethyl)-3-fluorobenzene(0.9 g) was added, and the mixture was stirred at 150° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by silica gel columnchromatography was dissolved in dimethyl sulfoxide (5 mL), and added toa mixture of hydroxylammonium chloride (0.64 g), sodium hydrogencarbonate (0.92 g) and dimethyl sulfoxide (20 mL) previously stirred at40° C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,and diluted with ethyl acetate. The mixture was washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.18 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.14 g,10%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.20-1.32 (2H, m),1.36-1.48 (2H, m), 2.41 (3H, s), 2.91-3.04 (2H, m), 3.26-3.42 (2H, m),3.87 (2H, s), 4.10-4.22 (2H, m), 7.03-7.14 (3H, m), 7.20-7.27 (4H, m),7.29-7.40 (1H, m), 7.47-7.58 (2H, m), 7.62-7.72 (2H, m), 11.86-12.78(1H, m)

Example 98

6-butyl-3-[2-(4-fluorophenyl)ethyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-(2-bromoethyl)-4-fluorobenzene(0.9 g) was added, and the mixture was stirred at 150° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by silica gel columnchromatography was dissolved in dimethyl sulfoxide (5 mL), and added toa mixture of hydroxylammonium chloride (0.9 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (20 mL) previously stirred at40° C. for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.29 g,16%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.12-1.31 (2H, m),1.36-1.47 (2H, m), 2.41 (3H, s), 2.90-3.00 (2H, m), 3.34 (2H, s), 3.87(2H, s), 4.07-4.17 (2H, m), 7.09-7.17 (2H, m), 7.22 (4H, s), 7.24-7.30(2H, m), 7.47-7.58 (2H, m), 7.63-7.71 (2H, m), 12.17-12.63 (1H, m)

Example 993-(2,3-dihydro-1-benzofuran-5-yl)-6-(ethoxymethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

99a)4′-{[4-(ethoxymethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 4-ethoxy-3-oxobutanoate (15.0 g) and tetrahydrofuran(150 mL) was ice-cooled to 0° C., sodium hydride (2.58 g) was graduallyadded, and the mixture was stirred in situ for 30 min. To the mixturewas added 4′-(bromomethyl)biphenyl-2-carbonitrile (11.7 g), and themixture was stirred for 30 min. Thereafter, the temperature of themixture was gradually raised to room temperature, and the mixture wasstirred for 4 hr. The solvent of the reaction mixture was evaporatedunder reduced pressure, and the residue was diluted with ethyl acetate.The diluted solution was washed with water and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. To an ice-cooled mixture of acetamidine hydrochloride(6.3 g) and methanol (50 mL) was added dropwise 28% sodiummethoxide-methanol solution (19.3 mL), and a mixture of theaforementioned residue (12.2 g), 1,4-dioxane (20 mL) and methanol (30mL) was added dropwise. The mixture was stirred at room temperature for12 hr. The solvent of the reaction mixture was evaporated under reducedpressure. The residue was diluted with ethyl acetate, washed with 0.1 Maqueous hydrochloric acid solution, water and saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give crude crystals. The crude crystals were washedwith diisopropyl ether to give the title compound as colorless crystals(8.3 g, 70%).

¹H NMR (300 MHz, CDCl₃) δ 1.23 (3H, t, J=7.0), 2.43 (3H, s), 3.59 (2H,q, J=7.0), 4.04 (2H, s), 4.45 (2H, s), 7.38-7.48 (6H, m), 7.62 (1H, td,J=7.7, 1.4), 7.74 (1H, dd, J=7.7, 0.9), 12.94 (1H, s)

99b)3-(2,3-dihydro-1-benzofuran-5-yl)-6-(ethoxymethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-{[4-(ethoxymethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(5.0 g), (2,3-dihydro-1-benzofuran-5-yl)boronic acid (5.0 g), copper(II)acetate (5.0 g), pyridine (5.0 mL), triethylamine (10 mL), molecularsieves 4 A (10 g) and dichloromethane (100 mL) was stirred for 2 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography. The obtained residue was dissolved in dimethyl sulfoxide(10 mL), and added to a mixture of hydroxylammonium chloride (7.3 g),sodium hydrogen carbonate (10.5 g) and dimethyl sulfoxide (42.5 mL)previously stirred at 40° C. for 30 min. The reaction mixture wasstirred at 90° C. for 16 hr, and diluted with ethyl acetate. The mixturewas washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (50 mL),N,N′-carbonyldiimidazole (1.9 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (1.7 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (3.5 g,62%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.09 (3H, t, J=7.1), 2.09 (3H, s), 3.23 (2H,t, J=8.8), 3.51 (2H, q, J=7.0), 3.90 (2H, s), 4.36 (2H, s), 4.61 (2H, t,J=8.8), 6.87 (1H, d, J=8.5), 7.05 (1H, dd, J=8.3, 2.3), 7.21 (3H, d,J=8.3), 7.28-7.32 (2H, m), 7.48-7.57 (2H, m), 7.63-7.71 (2H, m), 12.39(1H, s)

Example 1006-(cyclopropylmethyl)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

100a)4′-{[4-(cyclopropylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of ethyl 4-cyclopropyl-3-oxobutanoate (15.0 g) andtetrahydrofuran (150 mL) was ice-cooled to 0° C., sodium hydride (2.6 g)was gradually added, and the mixture was stirred in situ for 30 min. Tothe mixture was added 4′-(bromomethyl)biphenyl-2-carbonitrile (12.0 g),and the mixture was stirred for 30 min. Thereafter, the temperature ofthe mixture was gradually raised to room temperature, and the mixturewas stirred for 4 hr. The solvent of the reaction mixture was evaporatedunder reduced pressure, and the residue was diluted with ethyl acetate.The diluted solution was washed with water and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. To an ice-cooled mixture of acetamidine hydrochloride(6.4 g) and methanol (50 mL) was added dropwise 28% sodiummethoxide-methanol solution (20 mL), and a mixture of the aforementionedresidue (12.0 g), 1,4-dioxane (20 mL) and methanol (30 mL) was addeddropwise. The mixture was stirred at room temperature for 12 hr. Thesolvent of the reaction mixture was evaporated under reduced pressure.The residue was diluted with ethyl acetate, washed with 0.1 M aqueoushydrochloric acid solution, water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give crude crystals. The crude crystals were washed withdiisopropyl ether to give the title compound as colorless crystals (8.3g, 69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.08 (2H, q, J=4.8), 0.34 (2H, ddd, J=8.0,5.8, 4.0), 0.93-1.06 (1H, m), 2.27 (3H, s), 2.42 (2H, d, J=6.4), 3.84(2H, s), 7.31 (2H, d, J=8.0), 7.46 (2H, d, J=8.3), 7.52-7.60 (2H, m),7.73-7.80 (1H, m), 7.92 (1H, d, J=8.0), 12.19 (1H, s)

100b)6-(cyclopropylmethyl)-3-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-{[4-(cyclopropylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), (2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.0 g), copper(II)acetate (1.0 g), pyridine (1.0 mL), triethylamine (1.0 mL), molecularsieves 4 A (2.0 g) and dichloromethane (15 mL) was stirred for 6 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography. The obtained residue was dissolved in dimethyl sulfoxide(2.5 mL), and added to a mixture of hydroxylammonium chloride (1.8 g),sodium hydrogen carbonate (2.5 g) and dimethyl sulfoxide (10 mL)previously stirred at 40° C. for 30 min. The reaction mixture wasstirred at 90° C. for 16 hr, and diluted with ethyl acetate. The mixturewas washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (50 mL),N,N′-carbonyldiimidazole (0.44 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.61 g,46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.06-0.20 (2H, m), 0.38 (2H, ddd, J=8.0,5.8, 4.1), 0.97-1.07 (2H, m), 2.07-2.14 (3H, m), 2.45 (1H, d, J=6.8),3.23 (2H, s), 3.84 (2H, s), 4.61 (2H, t, J=8.8), 6.87 (1H, d, J=8.3),7.07 (1H, dd, J=8.5, 2.3), 7.19-7.27 (5H, m), 7.48-7.57 (2H, m),7.62-7.72 (2H, m), 12.40 (1H, s)

Example 101

6-(cyclopropylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

A mixture of4′-{[4-(cyclopropylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), phenylboronic acid (1.0 g), copper(II) acetate (1.0 g),pyridine (1.0 mL), triethylamine (1.0 mL), molecular sieves 4 A (2.0 g)and dichloromethane (15 mL) was stirred for 6 days. The reaction mixturewas diluted with ethyl acetate, and the insoluble material was filteredoff. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography. The obtainedresidue was dissolved in dimethyl sulfoxide (2.5 mL), and added to amixture of hydroxylammonium chloride (1.8 g), sodium hydrogen carbonate(2.5 g) and dimethyl sulfoxide (10 mL) previously stirred at 40° C. for30 min. The reaction mixture was stirred at 90° C. for 16 hr, anddiluted with ethyl acetate. The mixture was washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (50 mL), N,N′-carbonyldiimidazole (0.44 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.91 g,74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.10-0.17 (2H, m), 0.39 (2H, ddd, J=8.0,5.7, 4.1), 1.03 (1H, s), 2.07 (3H, s), 2.46 (1H, s), 3.34 (1H, s), 3.86(2H, s), 7.24 (4H, q, J=8.3), 7.37-7.43 (2H, m), 7.50 (2H, d, J=7.0),7.55 (3H, td, J=7.4, 1.6), 7.63-7.72 (2H, m), 12.40 (1H, s)

Example 1023-benzyl-6-butyl-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

102a)4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A solution of 2-methoxyethanimidamide hydrochloride (10 g), 28% sodiummethoxide (24 mL) and methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (15 g) in methanol(150 mL) and 1,4-dioxane (50 mL) was stirred overnight. The solvent wasevaporated under reduced pressure, and water and acetic acid were added.The precipitated solid was collected by filtration, and washed withwater and diethyl ether to give the title compound (11 g, 71%) as apale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.2), 1.19-1.34 (2H, m),1.37-1.51 (2H, m), 2.47-2.57 (2H, m), 3.33 (3H, s), 3.88 (2H, s), 4.23(2H, s), 7.33 (2H, d, J=8.2), 7.44-7.62 (4H, m), 7.73-7.81 (1H, m),7.90-7.95 (1H, m), 12.38 (1H, s)

102b)4′-{[1-benzyl-4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A solution of4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(4.5 g), benzyl bromide (1.5 mL) and cesium carbonate (4.2 g) inN,N-dimethylacetamide (45 mL) was stirred overnight. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (1.8 g, 32%) as a colorlessliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.89 (3H, t, J=7.3), 1.29-1.44 (2H, m),1.53-1.67 (2H, m), 2.73-2.82 (2H, m), 3.54 (3H, s), 4.06 (2H, s), 4.57(2H, s), 5.45 (2H, s), 7.21 (2H, d, J=8.1), 7.24-7.36 (5H, m), 7.37-7.51(4H, m), 7.58-7.67 (1H, m), 7.75 (1H, dd, J=7.7, 1.3)

102c)3-benzyl-6-butyl-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.6 g), sodium hydrogencarbonate (3.8 g) and dimethyl sulfoxide (18 mL) was stirred at 50° C.for 30 min,4′-{[1-benzyl-4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.8 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (18 mL), N,N′-carbonyldiimidazole (0.92 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.85 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (1.4 g, 69%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.2), 1.20-1.37 (2H, m),1.42-1.56 (2H, m), 2.65-2.74 (2H, m), 3.38 (3H, s), 4.02 (2H, s), 4.44(2H, s), 5.44 (2H, s), 7.12-7.73 (13H, m), 12.4 (1H, s)

Example 1033-benzyl-6-butyl-2-(fluoromethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

103a)4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

4′-{[4-Butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.0 g) was dissolved in dichloromethane (20 mL), and 1.0 M borontribromide dichloromethane solution (1.0 M, 16 mL) was added at 0° C.After stirring at room temperature for 3 hr, water was added, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue wascrystallized from ethyl acetate and diethyl ether to give the titlecompound (1.7 g, 86%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.89 (3H, t, J=7.2), 1.28-1.43 (2H, m),1.49-1.63 (2H, m), 2.57-2.68 (2H, m), 3.74 (1H, s), 3.96 (2H, s), 4.56(2H, s), 7.30-7.51 (6H, m), 7.57-7.67 (1H, m), 7.74 (1H, dd, J=7.7,0.94), 11.95 (1H, s)

103b)4′-{[1-benzyl-4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A solution of4′-{[4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.4 g), benzyl bromide (0.49 mL) and cesium carbonate (1.3 g) inN,N-dimethylacetamide (14 mL) was stirred for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.86 g, 49%) as a colorlessliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.92 (3H, t, J=7.2), 1.31-1.46 (2H, m),1.56-1.70 (2H, m), 2.62-2.73 (2H, m), 4.04 (2H, s), 4.32 (1H, t, J=4.2),4.48 (2H, d, J=3.9), 5.15 (2H, s), 7.16-7.22 (2H, m), 7.27-7.52 (9H, m),7.58-7.67 (1H, m), 7.75 (1H, dd, J=7.7, 0.94)

103c)4′-{[1-benzyl-4-butyl-2-(fluoromethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

4′-{[1-Benzyl-4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.86 g) was dissolved in dichloromethane (20 mL), andbis(2-methoxyethyl)aminosulfur trifluoride (0.34 mL) was added −78° C.The mixture was stirred at 0° C. for 3 hr, a saturated aqueous sodiumhydrogen carbonate solution was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.35 g, 41%) as a colorlessliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.92 (3H, t, J=7.2), 1.31-1.46 (2H, m),1.53-1.66 (2H, m), 2.61-2.69 (2H, m), 4.04 (2H, s), 5.13 (1H, s), 5.29(1H, s), 5.42 (2H, s), 7.17-7.23 (2H, m), 7.27-7.52 (9H, m), 7.58-7.67(1H, m), 7.75 (1H, dd, J=7.7, 0.94)

103d)3-benzyl-6-butyl-2-(fluoromethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (3.5 mL) was stirred at 50° C.for 30 min,4′-{[1-benzyl-4-butyl-2-(fluoromethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.35 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (3.5 mL), N,N′-carbonyldiimidazole (0.18 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.17 g, 42%) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.2), 1.33-1.48 (2H, m),1.51-1.80 (2H, m), 2.63-2.73 (2H, m), 3.98 (2H, s), 5.12 (1H, s), 5.28(1H, s), 5.34 (2H, s), 7.12-7.18 (2H, m), 7.23-7.51 (9H, m), 7.55-7.63(1H, m), 7.82 (1H, dd, J=7.7, 1.3)

3-Benzyl-6-butyl-2-(fluoromethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-benzyl-6-butyl-2-(fluoromethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   3-benzyl-6-butyl-2-(fluoromethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   3-benzyl-6-butyl-2-(fluoromethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   3-benzyl-6-butyl-2-(fluoromethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   3-benzyl-6-butyl-2-(fluoromethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 104

3-benzyl-6-butyl-2-(hydroxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.75 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-{[1-benzyl-4-butyl-2-(hydroxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.18 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.20 g, 35%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.2), 1.22-1.38 (2H, m),1.42-1.55 (2H, m), 2.52-2.60 (2H, m), 3.91 (2H, s), 4.37 (2H, d, J=5.7),5.35 (2H, s), 5.60 (1H, t, J=5.7), 7.12-7.40 (9H, m), 7.53 (2H, dd,J=15.7, 7.7), 7.62-7.73 (2H, m), 12.37 (1H, s)

Example 1053-benzyl-6-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

105a)4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A solution of propanimidamide hydrochloride (3.9 g), 28% sodiummethoxide (11 mL) and methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (6.5 g) in methanol(65 mL) was stirred overnight. The solvent was evaporated under reducedpressure, and water and acetic acid were added. The precipitated solidwas collected by filtration, and washed with water and diethyl ether togive the title compound (5.5 g, 83%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.5), 1.17 (3H, t, J=7.5),1.21-1.34 (2H, m), 1.37-1.51 (2H, m), 2.45-2.57 (4H, m), 3.86 (2H, s),7.33 (2H, d, J=8.2), 7.48 (2H, d, J=8.2), 7.52-7.62 (2H, m), 7.74-7.81(1H, m), 7.89-7.96 (1H, m), 12.30 (1H, s)

105b)4′-[(1-benzyl-4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A solution of4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.5 g), benzyl bromide (0.58 mL) and cesium carbonate (1.6 g) inN,N-dimethylacetamide (15 mL) was stirred overnight. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (1.0 g, 59%) as a colorlessliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.92 (3H, t, J=7.25), 1.23 (3H, t, J=7.3),1.31-1.46 (2H, m), 1.55-1.68 (2H, m), 2.59-2.72 (4H, m), 4.01 (2H, s),5.32 (2H, s), 7.16 (2H, d, J=6.9), 7.22-7.51 (9H, m), 7.57-7.66 (1H, m),7.74 (1H, dd, J=7.7, 1.3)

105c)3-benzyl-6-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-[(1-benzyl-4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.58 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.53 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.80 g, 65%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.2), 1.09 (3H, t, J=7.2),1.21-1.37 (2H, m), 1.45-1.57 (2H, m), 2.48-2.58 (2H, m), 2.67 (2H, q,J=7.1), 3.92 (2H, s), 5.31 (2H, s), 7.14 (2H, d, J=6.9), 7.20-7.40 (7H,m), 7.48-7.59 (2H, m), 7.62-7.73 (2H, m), 12.39 (1H, s)

3-Benzyl-6-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-benzyl-6-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   3-benzyl-6-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   3-benzyl-6-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   3-benzyl-6-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   3-benzyl-6-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 1066-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

106a)4′-[(4-butyl-2-ethyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.5 g), phenylboronic acid (0.99 g), copper(II) acetate (1.5 g),pyridine (1.6 mL), triethylamine (2.8 mL), molecular sieves 4 A (1.5 g)and dichloromethane (30 mL) was stirred for 6 days. The reaction mixturewas diluted with ethyl acetate, and the insoluble material was filteredoff. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (1.0 g, 55%) as a colorless liquid.

¹H NMR (300 MHz, CDCl₃) δ 0.95 (3H, t, J=7.2), 1.15 (3H, t, J=7.4),1.35-1.51 (2H, m), 1.57-1.73 (2H, m), 2.36 (2H, q, J=7.4), 2.69 (2H, q,J=7.2), 3.97 (2H, s), 7.19-7.28 (2H, m), 7.36-7.57 (9H, m), 7.57-7.65(1H, m), 7.74 (1H, dd, J=7.7, 1.1)

106b)6-butyl-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-[(4-butyl-2-ethyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.54 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.50 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.68 g, 60%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.26-1.41 (2H, m), 1.46-1.60 (2H, m), 2.26 (2H, q, J=7.2), 2.56 (2H, m),3.87 (2H, s), 7.19-7.32 (4H, m), 7.34-7.40 (2H, m), 7.45-7.58 (5H, m),7.62-7.73 (2H, m), 12.39 (1H, s)

Example 1073-benzyl-6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

107a)4′-[(4-butyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A solution of methyl imidocarbamate sulfate (10 g), 28% sodium methoxide(29 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(9.8 g) in methanol (100 mL) was stirred at 70° C. overnight. Thesolvent was evaporated under reduced pressure, and water and acetic acidwere added. The precipitated solid was collected by filtration, andwashed with water and diethyl ether to give the title compound (3.9 g,37%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.2), 1.20-1.34 (2H, m),1.40-1.54 (2H, m), 2.43-2.53 (2H, m), 3.82 (2H, s), 3.86 (3H, s),7.28-7.65 (6H, m), 7.73-7.82 (1H, m), 7.90-7.96 (1H, m), 12.26 (1H, s)

107b)4′-[(1-benzyl-4-butyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A solution of4′-[(4-butyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.5 g), benzyl bromide (0.53 mL) and cesium carbonate (1.4 g) inN,N-dimethylformamide (15 mL) was stirred overnight. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.93 g, 50%) as a colorlessliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.2), 1.27-1.41 (2H, m),1.51-1.65 (2H, m), 2.49-2.58 (2H, m), 3.94 (2H, s), 3.97 (3H, s), 5.18(2H, s), 7.22-7.52 (11H, m), 7.57-7.65 (1H, m), 7.74 (1H, dd, J=7.7,1.3)

107c)3-benzyl-6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.0 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-[(1-benzyl-4-butyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.93 g) was added, and the mixture was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.32 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.18 g, 17%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.20-1.36 (2H, m),1.42-1.56 (2H, m), 2.44-2.54 (2H, m), 3.85 (2H, s), 3.91 (3H, s), 5.11(2H, s), 7.17-7.39 (9H, m), 7.46-7.58 (2H, m), 7.62-7.73 (2H, m), 12.38(1H, s)

3-Benzyl-6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-benzyl-6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   3-benzyl-6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   3-benzyl-6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   3-benzyl-6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   3-benzyl-6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 1086-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

108a)4′-[(4-butyl-2-methoxy-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methoxy-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.0 g), phenylboronic acid (1.3 g), copper(II) acetate (2.0 g),pyridine (2.2 mL), triethylamine (3.7 mL), molecular sieves 4 A (2.0 g)and dichloromethane (54 mL) was stirred overnight. The reaction mixturewas diluted with ethyl acetate, and the insoluble material was filteredoff. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (1.6 g, 65%) as a colorless liquid.

¹H NMR (300 MHz, CDCl₃) δ 0.95 (3H, t, J=7.3), 1.35-1.49 (2H, m),1.60-1.72 (2H, m), 2.64 (2H, q, J=7.3), 3.88 (3H, s), 3.94 (2H, s),7.20-7.25 (2H, m), 7.36-7.52 (9H, m), 7.57-7.65 (1H, m), 7.74 (1H, dd,J=7.7, 1.1)

108b)6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.4 g), sodium hydrogencarbonate (3.5 g) and dimethyl sulfoxide (16 mL) was stirred at 50° C.for 30 min,4′-[(4-butyl-2-methoxy-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.6 g) was added, and the mixture was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (16 mL), N,N′-carbonyldiimidazole (0.57 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.40 g, 22%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.3), 1.26-1.40 (2H, m),1.47-1.61 (2H, m), 2.48-2.56 (2H, m), 3.81 (3H, s), 3.84 (2H, s),7.19-7.35 (6H, m), 7.40-7.58 (5H, m), 7.63-7.72 (2H, m), 12.39 (1H, s)

6-Butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one    sodium salt-   6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one    potassium salt-   6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one    hydrochloride-   6-butyl-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one    hydrobromide

Example 1096-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

109a)4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(5.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (4.4 g), copper(II)acetate (4.9 g), pyridine (5.4 mL), triethylamine (9.4 mL), molecularsieves 4 A (10 g) and dichloromethane (200 mL) was stirred for 2 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound (5.4 g, 82%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.95 (3H, t, J=7.2), 1.15 (3H, t, J=7.2),1.34-1.50 (2H, m), 1.59-1.72 (2H, m), 2.41 (2H, q, J=7.4), 2.63-2.73(2H, m), 3.21-3.31 (2H, m), 3.90-4.03 (2H, m), 4.64 (2H, t, J=9.0),6.83-6.97 (2H, m), 7.02 (1H, d, J=1.5), 7.37-7.52 (6H, m), 7.57-7.66(1H, m), 7.74 (1H, dd, J=7.7, 0.94)

109b)6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (9.4 g), sodium hydrogencarbonate (13.6 g) and dimethyl sulfoxide (60 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(5.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (60 mL), N,N′-carbonyldiimidazole (3.3 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (3.0 mL) were added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography and recrystallized from dichloromethane and diisopropylether to give the title compound (4.5 g, 75%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.3), 1.05 (3H, t, J=7.3),1.25-1.40 (2H, m), 1.46-1.59 (2H, m), 2.31 (2H, q, J=7.3), 2.47-2.59(2H, m), 3.23 (2H, t, J=8.7), 3.86 (2H, s), 4.61 (2H, t, J=8.7), 6.86(1H, d, J=8.4), 7.04 (1H, dd, J=8.4, 2.2), 7.18-7.31 (5H, m), 7.47-7.58(2H, m), 7.62-7.73 (2H, m), 12.39 (1H, s)

Example 1106-butyl-2-ethyl-3-(2-hydroxy-3,3-dimethylbutyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

110a)4′-{[4-butyl-1-(3,3-dimethyl-2-oxobutyl)-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A solution of4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(20 g), 1-bromo-3,3-dimethylbutan-2-one (8.7 mL) and cesium carbonate(21 g) in N,N-dimethylformamide (200 mL) was stirred for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (3.8 g, 15%) as a colorlessliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3), 1.22-1.43 (14H, m),1.53-1.66 (2H, m), 2.49 (2H, q, J=7.3), 2.56-2.63 (2H, m), 3.95 (2H, s),5.06 (2H, s), 7.29-7.50 (6H, m), 7.57-7.65 (1H, m), 7.73 (1H, dd, J=7.7,0.94)

110b)6-butyl-2-ethyl-3-(2-hydroxy-3,3-dimethylbutyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

4′-{[4-Butyl-1-(3,3-dimethyl-2-oxobutyl)-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(3.8 g) was dissolved in methanol (40 mL) and tetrahydrofuran (40 mL),and sodium borohydride (0.92 g) was added at 0° C. After stirring for 2hr, water was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in dimethyl sulfoxide (40 mL),hydroxylammonium chloride (5.6 g) and sodium hydrogen carbonate (8.2 g)were added, and the mixture was stirred at 90° C. overnight. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (1.3 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL) were added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (3.5 g, 81%) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 0.92-0.99 (12H, m), 1.32 (3H, t, J=7.3),1.36-1.51 (2H, m), 1.64-1.77 (2H, m), 2.67-2.86 (4H, m), 3.79-3.89 (3H,m), 4.30 (1H, dd, J=13.9, 10.7), 7.20-7.31 (5H, m), 7.43-7.50 (2H, m),7.57-7.64 (1H, m), 7.78-7.83 (1H, m)

Example 111

6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

6-Butyl-2-ethyl-3-(2-hydroxy-3,3-dimethylbutyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(2.9 g) was dissolved in dichloromethane (60 mL),1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (2.8 g) wasadded, and the mixture was stirred for 1 hr. A saturated aqueous sodiumhydrogen carbonate solution and sodium thiosulfate 5 hydrate were added,and the mixture was further stirred for 1 hr. The reaction mixture wasextracted with ethyl acetate, washed with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (2.9 g, 100%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.1), 1.14 (3H, t, J=7.1),1.21 (9H, s), 1.23-1.39 (2H, m), 1.47-1.60 (2H, m), 2.47-2.59 (4H, m),3.79 (2H, s), 5.14 (2H, s), 7.05-7.09 (2H, m), 7.16-7.22 (2H, m),7.25-7.48 (4H, m)

Example 1126-butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

112a)4′-[(4-butyl-2-cyclopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A solution of cyclopropanecarboxylmidamide hydrochloride (7.7 g), 28%sodium methoxide (17 mL) and methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (10 g) in methanol(100 mL) was stirred overnight. The solvent was evaporated under reducedpressure, and water and 1 M hydrochloric acid were added. Theprecipitated solid was collected by filtration, and washed with waterand diethyl ether to give the title compound (8.0 g, 73%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (3H, t, J=7.3), 0.98 (4H, d, J=6.0),1.15-1.30 (2H, m), 1.34-1.45 (2H, m), 1.82-1.93 (1H, m), 2.42 (2H, t,J=7.3), 3.83 (2H, s), 7.32 (2H, d, J=7.9), 7.47 (2H, d, J=7.9),7.52-7.61 (2H, m), 7.77 (1H, t, J=7.5), 7.92 (1H, d, J=7.5), 12.52 (1H,s)

112b)4′-{[4-butyl-2-cyclopropyl-1-(2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-cyclopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.58 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.49 g), copper(II)acetate (0.55 g), pyridine (0.61 mL), triethylamine (1.1 mL), molecularsieves 4 A (1.2 g) and dichloromethane (12 mL) was stirred for 2 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound (0.75 g, 100%) as apale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 0.83 (2H, dd, J=7.7, 3.9), 0.93 (3H, t,J=7.1), 1.15-1.21 (2H, m), 1.30-1.65 (5H, m), 2.57-2.64 (2H, m),3.20-3.34 (2H, m), 3.88-4.00 (2H, m), 4.64 (2H, t, J=8.7), 6.86-6.90(1H, m), 6.99-7.04 (1H, m), 7.11 (1H, d, J=1.89), 7.36-7.50 (6H, m),7.57-7.65 (1H, m), 7.73 (1H, d, J=7.5)

112c)6-butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (12 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-2-cyclopropyl-1-(2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.75 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (12 mL), N,N′-carbonyldiimidazole (0.37 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography and recrystallized from dichloromethane and diisopropylether to give the title compound (0.70 g, 83%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.80-0.87 (5H, m), 0.95-1.13 (2H, m),1.21-1.52 (5H, m), 2.43-2.53 (2H, m), 3.24 (2H, m), 3.84 (2H, s),4.57-4.66 (2H, m), 6.89 (1H, d, J=8.4), 7.07 (1H, dd, J=8.4, 2.2),7.18-7.29 (5H, m), 7.47-7.58 (2H, m), 7.61-7.72 (2H, m), 12.38 (1H, s)

6-Butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-2-cyclopropyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 1136-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

113a)4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile

A solution of propanimidamide hydrochloride (7.5 g), 28% sodiummethoxide (23 mL) and methyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (8.4 g) inmethanol (84 mL) was stirred overnight. The solvent was evaporated underreduced pressure, and water and 1 M hydrochloric acid were added. Theprecipitated solid was collected by filtration, and washed with waterand diethyl ether to give the title compound (4.7 g, 53%) as apale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.13-1.34 (5H, m),1.39-1.52 (2H, m), 2.43-2.59 (4H, m), 3.84 (2H, s), 7.21 (1H, t, J=7.9),7.28-7.34 (1H, m), 7.42 (1H, dd, J=10.9, 1.8), 7.55-7.65 (2H, m),7.74-7.83 (1H, m), 7.91-7.98 (1H, m), 12.33 (1H, s)

113b)4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.58 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.49 g), copper(II)acetate (0.55 g), pyridine (0.61 mL), triethylamine (1.1 mL), molecularsieves 4 A (1.2 g) and dichloromethane (12 mL) was stirred for 2 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound (0.60 g, 79%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.3), 1.16 (3H, t, J=7.3),1.33-1.50 (2H, m), 1.57-1.72 (2H, m), 2.42 (2H, q, J=7.3), 2.63-2.72(2H, m), 3.16-3.36 (2H, m), 3.98 (2H, s), 4.64 (2H, t, J=9.2), 6.84-6.97(2H, m), 7.03 (1H, d, J=1.7), 7.18-7.25 (2H, m), 7.40-7.49 (3H, m),7.58-7.67 (1H, m), 7.75 (1H, dd, J=7.8, 0.85)

113c)6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.60 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.37 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography and recrystallized from dichloromethane and diisopropylether to give the title compound (0.62 g, 92%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.3), 1.06 (3H, t, J=7.3),1.22-1.39 (2H, m), 1.47-1.60 (2H, m), 2.32 (2H, q, J=7.3), 2.47-2.57(2H, m), 3.22 (2H, t, J=8.7), 3.85 (2H, s), 4.60 (2H, t, J=8.7), 6.86(1H, d, J=8.2), 6.98-7.07 (2H, m), 7.11-7.21 (3H, m), 7.50-7.62 (2H, m),7.64-7.74 (2H, m), 12.46 (1H, s)

Example 1146-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

114a)4′-[(4-butyl-6-oxo-2-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A solution of butanimidamide hydrochloride (3.5 g), 28% sodium methoxide(8.7 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate(5.0 g) in methanol (50 mL) was stirred overnight. The solvent wasevaporated under reduced pressure, and water and 1 M hydrochloric acidwere added. The precipitated solid was collected by filtration, andwashed with water and diethyl ether to give the title compound (4.5 g,82%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (3H, t, J=7.3), 0.90 (3H, t, J=7.3),1.19-1.33 (2H, m), 1.38-1.51 (2H, m), 1.60-1.74 (2H, m), 2.43-2.55 (4H,m), 3.86 (2H, s), 7.33 (2H, d, J=8.3), 7.48 (2H, d, J=8.3), 7.52-7.62(2H, m), 7.72-7.81 (1H, m), 7.92 (1H, d, J=7.9), 12.30 (1H, s)

114b)4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-6-oxo-2-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-6-oxo-2-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.58 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.49 g), copper(II)acetate (0.55 g), pyridine (0.61 mL), triethylamine (1.1 mL), molecularsieves 4 A (1.2 g) and dichloromethane (12 mL) was stirred for 2 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound (0.59 g, 79%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.87 (3H, t, J=7.4), 0.94 (3H, t, J=7.2),1.34-1.49 (2H, m), 1.56-1.74 (4H, m), 2.31-2.39 (2H, m), 2.64-2.72 (2H,m), 3.27 (2H, t, J=8.7), 3.89-4.03 (2H, m), 4.57-4.72 (2H, m), 6.84-6.96(2H, m), 7.02 (1H, d, J=1.1), 7.36-7.51 (6H, m), 7.57-7.65 (1H, m), 7.74(1H, dd, J=7.7, 1.3)

114c)6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-6-oxo-2-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.59 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.37 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography and recrystallized from dichloromethane and diisopropylether to give the title compound (0.61 g, 92%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (3H, t, J=7.3), 0.86 (3H, t, J=7.3),1.22-1.39 (2H, m), 1.46-1.66 (2H, m), 2.27 (2H, t, J=7.4), 2.47-2.59(4H, m), 3.23 (2H, t, J=8.6), 3.86 (2H, s), 4.61 (2H, t, J=8.6), 6.87(1H, d, J=8.2), 7.03 (1H, dd, J=8.2, 2.2), 7.16-7.30 (5H, m), 7.46-7.59(2H, m), 7.62-7.72 (2H, m), 12.39 (1H, s)

Example 1156-butyl-2-(cyclopropylmethyl)-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

115a)4′-{[4-butyl-2-(cyclopropylmethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A solution of 2-cyclopropylethanimidamide hydrochloride (3.9 g), 28%sodium methoxide (8.7 mL) and methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (5.0 g) in methanol(50 mL) was stirred overnight. The solvent was evaporated under reducedpressure, and water and 1 M hydrochloric acid were added. Theprecipitated solid was collected by filtration, and washed with waterand diethyl ether to give the title compound (4.3 g, 76%) as apale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.24 (2H, q, J=4.8), 0.42-0.49 (2H, m), 0.82(3H, t, J=7.3), 1.02-1.18 (1H, m), 1.20-1.34 (2H, m), 1.40-1.52 (2H, m),2.39 (2H, d, J=7.1), 2.46-2.55 (2H, m), 3.87 (2H, s), 7.34 (2H, d,J=8.3), 7.45-7.51 (2H, m), 7.52-7.62 (2H, m), 7.73-7.81 (1H, m), 7.92(1H, d, J=6.8), 12.30 (1H, s)

115b)4′-{[4-butyl-2-(cyclopropylmethyl)-1-(2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-butyl-2-(cyclopropylmethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.58 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.49 g), copper(II)acetate (0.55 g), pyridine (0.61 mL), triethylamine (1.1 mL), molecularsieves 4 A (1.2 g) and dichloromethane (12 mL) was stirred for 2 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound (0.59 g, 76%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.09 (2H, q, J=4.8), 0.42-0.52 (2H, m),0.88-1.04 (4H, m), 1.35-1.51 (2H, m), 1.60-1.73 (2H, m), 2.34 (2H, d,J=6.5), 2.65-2.74 (2H, m), 3.21-3.31 (2H, m), 3.96 (2H, d, J=2.6),4.59-4.70 (2H, m), 6.83-6.98 (2H, m), 7.03 (1H, s), 7.36-7.51 (6H, m),7.57-7.66 (1H, m), 7.74 (1H, d, J=7.7)

115c)6-butyl-2-(cyclopropylmethyl)-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.0 g), sodium hydrogencarbonate (1.5 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-2-(cyclopropylmethyl)-1-(2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.59 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.37 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography and recrystallized from dichloromethane and diisopropylether to give the title compound (0.54 g, 82%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.00-0.08 (2H, m), 0.36-0.44 (2H, m), 0.86(3H, t, J=7.25), 0.87-1.00 (1H, m), 1.26-1.40 (2H, m), 1.47-1.61 (2H,m), 2.25 (2H, d, J=6.5), 2.52-2.59 (2H, m), 3.23 (2H, t, J=8.6), 3.86(2H, s), 4.61 (2H, t, J=8.6), 6.86 (1H, d), 7.03 (1H, dd, J=8.2, 2.2),7.17-7.32 (5H, m), 7.47-7.59 (2H, m), 7.62-7.73 (2H, m), 12.39 (1H, s)

Example 1166-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-(2-methoxyethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

116a)1′-{[4-butyl-2-(2-methoxyethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A solution of 3-methoxypropanimidamide hydrochloride (4.0 g), 28% sodiummethoxide (8.7 mL) and methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (5.0 g) in methanol(50 mL) was stirred overnight. The solvent was evaporated under reducedpressure, and water and 1 M hydrochloric acid were added. Theprecipitated solid was collected by filtration, and washed with waterand diethyl ether to give the title compound (2.5 g, 44%) as apale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.1), 1.18-1.34 (2H, m),1.37-1.52 (2H, m), 2.46-2.54 (2H, m), 2.75 (2H, t, J=6.6), 3.23 (3H, s),3.68 (2H, t, J=6.4), 3.86 (2H, s), 7.33 (2H, d, J=7.9), 7.48 (2H, d,J=7.9), 7.51-7.61 (2H, m), 7.77 (1H, t, J=7.5), 7.92 (1H, d, J=7.9),12.34 (1H, s)

116b)4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-(2-methoxyethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-butyl-2-(2-methoxyethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.5 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (2.0 g), copper(II)acetate (2.3 g), pyridine (2.5 mL), triethylamine (4.3 mL), molecularsieves 4 A (5.0 g) and dichloromethane (50 mL) was stirred for 2 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound (2.3 g, 72%) as a pale-yellowliquid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.3), 1.25-1.39 (2H, m),1.47-1.60 (2H, m), 2.56 (4H, q, J=7.0), 3.16 (3H, s), 3.23 (2H, t,J=8.7), 3.61 (2H, t, J=6.8), 3.90 (2H, s), 4.61 (2H, t, J=8.9), 6.88(1H, d, J=8.3), 7.04 (1H, dd, J=8.3, 2.2), 7.20 (1H, d, J=1.89),7.34-7.40 (2H, m), 7.45-7.62 (5H, m), 7.93 (1H, d, J=7.9)

116c)6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-(2-methoxyethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (3.1 g), sodium hydrogencarbonate (4.5 g) and dimethyl sulfoxide (24 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-(2-methoxyethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.3 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (24 mL), N,N′-carbonyldiimidazole (1.1 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.0 mL) were added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (2.0 g, 55%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.24-1.41 (2H, m),1.44-1.59 (2H, m), 2.44-2.60 (4H, m), 3.16 (3H, s), 3.23 (2H, t, J=8.5),3.61 (2H, t, J=6.8), 3.86 (2H, s), 4.61 (2H, t, J=8.7), 6.88 (1H, d,J=8.2), 7.04 (1H, d, J=8.2), 7.16-7.31 (5H, m), 7.47-7.59 (2H, m),7.63-7.73 (2H, m), 12.40 (1H, s)

Example 117

6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-(2-hydroxyethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-(2-methoxyethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(1.0 g), 2-butanone (10 mL), water (6 mL) and concentrated hydrochloricacid (2 mL) was stirred at 100° C. for 1 hr. The reaction solution wascooled to room temperature, and the solvent was removed under reducedpressure. Water was added to the residue, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.57 g, 59%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.25-1.40 (2H, m),1.44-1.58 (2H, m), 2.44-2.59 (4H, m), 3.23 (2H, t, J=8.6), 3.67 (2H, q,J=6.4), 3.86 (2H, s), 4.53-4.67 (3H, m), 6.88 (1H, d, J=8.4), 7.00-7.08(1H, m), 7.17-7.31 (5H, m), 7.40-7.60 (2H, m), 7.62-7.73 (2H, m), 12.40(1H, s)

Example 1186-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

118a)4′-[(4-butyl-2-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A solution of 2-methylpropanimidamide hydrochloride (10 g), 28% sodiummethoxide (25 mL) and methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (14 g) in methanol(140 mL) and 1,4-dioxane (70 mL) was stirred overnight. The solvent wasevaporated under reduced pressure, and water and 1 M hydrochloric acidwere added. The precipitated solid was collected by filtration, andwashed with water and diethyl ether to give the title compound (9.7 g,62%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.19 (6H, d, J=6.8),1.21-1.35 (2H, m), 1.40-1.53 (2H, m), 2.46-2.56 (2H, m), 2.72-2.86 (1H,m), 3.86 (2H, s), 7.34 (2H, d, J=7.9), 7.48 (2H, d, J=7.9), 7.52-7.61(2H, m), 7.73-7.81 (1H, m), 7.92 (1H, d, J=7.5), 12.25 (1H, s)

118b)4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.85 g), copper(II)acetate (0.94 g), pyridine (1.1 mL), triethylamine (1.8 mL), molecularsieves 4 A (2.0 g) and dichloromethane (12 mL) was stirred for 2 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound (1.1 g, 79%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.95 (3H, t, J=7.3), 1.15 (6H, d, J=6.7),1.34-1.49 (2H, m), 1.60-1.74 (2H, m), 2.62-2.76 (3H, m), 3.22-3.31 (2H,m), 3.95 (2H, d, J=2.8), 4.64 (2H, t, J=8.9), 6.90 (2H, q, J=8.5), 7.02(1H, s), 7.36-7.52 (6H, m), 7.62 (1H, t, J=7.7), 7.74 (1H, d, J=7.7)

118c)6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogencarbonate (2.6 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.63 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.58 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.88 g, 60%) as a colorlesssolid.

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.3), 1.15 (6H, d, J=6.7),1.32-1.48 (2H, m), 1.56-1.72 (2H, m), 2.59-2.76 (3H, m), 3.27 (2H, t,J=8.2), 3.93 (2H, d, J=1.5), 4.64 (2H, t, J=9.3), 6.83-6.95 (2H, m),7.01 (1H, d, J=1.3), 7.30-7.40 (6H, m), 7.41-7.48 (1H, m), 7.53-7.59(1H, m)

6-Butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-isopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 1196-butyl-2-cyclopropyl-3-(4-ethoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

119a)4′-{[4-butyl-2-cyclopropyl-1-(4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-cyclopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-ethoxyphenyl)boronic acid (0.87 g), copper(II) acetate (0.95g), pyridine (1.1 mL), triethylamine (1.8 mL), molecular sieves 4 A (2.0g) and dichloromethane (20 mL) was stirred for 2 days. The reactionmixture was diluted with ethyl acetate, and the insoluble material wasfiltered off. The filtrate was concentrated under reduced pressure, theresidue was purified by silica gel column chromatography to give thetitle compound (1.1 g, 84%) as a pale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 0.77-0.86 (2H, m), 0.93 (3H, t, J=7.2),1.13-1.22 (2H, m), 1.30-1.66 (8H, m), 2.56-2.64 (2H, m), 3.94 (2H, s),4.07 (2H, q, J=6.9), 7.01 (2H, d, J=8.8), 7.20 (2H, d, J=8.6), 7.36-7.51(6H, m), 7.57-7.66 (1H, m), 7.74 (1H, dd, J=7.7, 1.1)

119b)6-butyl-2-cyclopropyl-3-(4-ethoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogencarbonate (2.6 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-2-cyclopropyl-1-(4-ethoxyphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.75 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.63 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.59 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography, and recrystallized from dichloromethane and diisopropylether to give the title compound (1.3 g, 97%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.77-0.88 (5H, m), 0.99-1.06 (2H, m),1.21-1.53 (8H, m), 2.43-2.53 (2H, m), 3.84 (2H, s), 4.08 (2H, q, J=6.9),7.07 (2H, d, J=8.8), 7.18-7.32 (6H, m), 7.30-7.60 (2H, m), 7.62-7.73(2H, m), 12.39 (1H, s)

Example 1206-butyl-2-cyclopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

120a)4′-[(4-butyl-2-cyclopropyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-cyclopropyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), phenylboronic acid (0.64 g), copper(II) acetate (0.95 g),pyridine (1.1 mL), triethylamine (1.8 mL), molecular sieves 4 A (2.0 g)and dichloromethane (20 mL) was stirred for 2 days. The reaction mixturewas diluted with ethyl acetate, and the insoluble material was filteredoff. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (0.80 g, 59%) as a pale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 0.76-0.86 (2H, m), 0.93 (3H, t, J=7.2),1.13-1.25 (2H, m), 1.26-1.46 (3H, m), 1.53-1.67 (2H, m), 2.57-2.66 (2H,m), 3.95 (2H, s), 7.29-7.35 (2H, m), 7.36-7.57 (9H, m), 7.57-7.66 (1H,m), 7.74 (1H, dd, J=7.7, 1.3)

120b)6-butyl-2-cyclopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.6 g) and dimethyl sulfoxide (8 mL) was stirred at 50° C.for 30 min,4′-[(4-butyl-2-cyclopropyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.80 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (8 mL), N,N′-carbonyldiimidazole (0.37 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography and recrystallized from dichloromethane and diisopropylether to give the title compound (0.62 g, 78%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.77-0.88 (5H, m), 1.00-1.08 (2H, m),1.22-1.37 (3H, m), 1.40-1.54 (2H, m), 2.44-2.54 (2H, m), 3.85 (2H, s),7.19-7.31 (4H, m), 7.38-7.44 (2H, m), 7.46-7.62 (5H, m), 7.62-7.73 (2H,m), 12.39 (1H, s)

Example 1213-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

121a)4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A solution of propanimidamide hydrochloride (20 g), 28% sodium methoxide(56 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (34g) in methanol (350 mL) was stirred overnight. The solvent wasevaporated under reduced pressure, and water and 1 M hydrochloric acidwere added. The precipitated solid was collected by filtration, andwashed with water and diethyl ether to give the title compound (27 g,82%) as a pale-yellow solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.1), 1.17 (3H, t, J=7.3),1.43-1.62 (2H, m), 2.43-2.58 (4H, m), 3.86 (2H, s), 7.34 (2H, d, J=7.9),7.48 (2H, d, J=7.9), 7.51-7.63 (2H, m), 7.77 (1H, t, J=7.6), 7.93 (1H,d, J=7.6), 12.31 (1H, s)

121b)4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (2.8 g), copper(II)acetate (3.1 g), pyridine (3.1 mL), triethylamine (3.4 mL), molecularsieves 4 A (6.0 g) and dichloromethane (60 mL) was stirred for 2 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound (4.0 g, 100%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.16 (3H, t, J=7.3),1.64-1.80 (2H, m), 2.33-2.48 (2H, m), 2.62-2.73 (2H, m), 3.12-3.34 (2H,m), 3.96 (2H, d, J=2.6), 4.50-4.72 (2H, m), 6.65-7.55 (9H, m), 7.58-7.67(1H, m), 7.74 (1H, d, J=7.7)

121c)3-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogencarbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C.for 30 min,4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(4.0 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (2.2 g, 48%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.25), 1.05 (3H, t, J=7.2),1.50-1.68 (2H, m), 2.31 (2H, q, J=7.2), 2.46-2.64 (2H, m), 3.23 (2H, t,J=8.4), 3.87 (2H, s), 4.61 (2H, t, J=8.6), 6.86 (1H, d, J=8.4), 7.04(1H, d, J=8.4), 7.18-7.32 (5H, m), 7.47-7.59 (2H, m), 7.62-7.74 (2H, m),12.38 (1H, s)

Example 1222-ethyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

122a)4′-{[2-ethyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (3.0 g),copper(II) acetate (3.1 g), pyridine (3.1 mL), triethylamine (3.4 mL),molecular sieves 4 A (6.0 g) and dichloromethane (60 mL) was stirred for2 days. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off. The filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound (4.1 g, 100%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.11-1.20 (3H, m),1.45-1.55 (3H, m), 1.64-1.80 (2H, m), 2.35-2.48 (2H, m), 2.63-2.73 (2H,m), 2.78-2.95 (1H, m), 3.29-3.42 (1H, m), 3.97 (2H, s), 4.93-5.10 (1H,m), 6.79-7.03 (3H, m), 7.36-7.53 (6H, m), 7.57-7.66 (1H, m), 7.74 (1H,d, J=7.7)

122b)2-ethyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogencarbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C.for 30 min,4′-{[2-ethyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(4.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (2.3 g, 49%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3), 1.02-1.13 (3H, m),1.39-1.47 (3H, m), 1.50-1.65 (2H, m), 2.25-2.37 (2H, m), 2.46-2.59 (2H,m), 2.77-2.91 (1H, m), 3.30-3.43 (1H, m), 3.86 (2H, s), 4.92-5.08 (1H,m), 6.83 (1H, d, J=8.2), 7.03 (1H, dd, J=8.2, 1.8), 7.13-7.33 (5H, m),7.46-7.59 (2H, m), 7.62-7.73 (2H, m), 12.38 (1H, s)

Example 1232-ethyl-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

123a)4′-{[2-ethyl-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g), 4-methoxyphenylboronic acid (2.5 g), copper(II) acetate (3.1g), pyridine (3.1 mL), triethylamine (3.4 mL), molecular sieves 4 A (6.0g) and dichloromethane (60 mL) was stirred for 2 days. The reactionmixture was diluted with ethyl acetate, and the insoluble material wasfiltered off. The filtrate was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography to give thetitle compound (4.0 g, 100%) as a pale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.14 (3H, t, J=7.3),1.64-1.79 (2H, m), 2.38 (2H, q, J=7.3), 2.63-2.72 (2H, m), 3.85 (3H, s),3.97 (2H, s), 6.98-7.07 (2H, m), 7.10-7.18 (2H, m), 7.37-7.52 (6H, m),7.58-7.66 (1H, m), 7.74 (1H, dd, J=7.7, 1.3)

123b)2-ethyl-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogencarbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C.for 30 min,4′-{[2-ethyl-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(4.0 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (2.2 g, 51%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.3),1.50-1.66 (2H, m), 2.28 (2H, q, J=7.3), 2.44-2.61 (2H, m), 3.82 (3H, s),3.87 (2H, s), 7.00-7.14 (2H, m), 7.18-7.34 (6H, m), 7.47-7.60 (2H, m),7.62-7.73 (2H, m), 12.38 (1H, s)

Example 1242-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenyl-6-propylpyrimidin-4(3H)-one

124a)4′-[(2-ethyl-6-oxo-1-phenyl-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g), phenylboronic acid (2.1 g), copper(II) acetate (3.1 g),pyridine (3.1 mL), triethylamine (3.4 mL), molecular sieves 4 A (6.0 g)and dichloromethane (60 mL) was stirred for 2 days. The reaction mixturewas diluted with ethyl acetate, and the insoluble material was filteredoff. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (3.6 g, 100%) as a pale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.15 (3H, t, J=7.3),1.65-1.82 (2H, m), 2.36 (2H, q, J=7.3), 2.63-2.75 (2H, m), 3.97 (2H, s),7.19-7.32 (4H, m), 7.37-7.67 (8H, m), 7.74 (1H, dd, J=7.7, 0.94)

124b)2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogencarbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C.for 30 min,4′-[(2-ethyl-6-oxo-1-phenyl-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (1.7 g, 40%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.3), 1.04 (3H, t, J=7.3),1.51-1.66 (2H, m), 2.26 (2H, q, J=7.3), 2.47-2.60 (2H, m), 3.88 (2H, s),7.19-7.41 (6H, m), 7.45-7.59 (5H, m), 7.63-7.73 (2H, m), 12.40 (1H, s)

Example 1252-ethyl-3-(4-ethoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

125a)4′-{[2-ethyl-1-(4-ethoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g), 4-ethoxyphenylboronic acid (2.8 g), copper(II) acetate (3.1 g),pyridine (3.1 mL), triethylamine (3.4 mL), molecular sieves 4 A (6.0 g)and dichloromethane (60 mL) was stirred for 2 days. The reaction mixturewas diluted with ethyl acetate, and the insoluble material was filteredoff. The filtrate was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography to give thetitle compound (4.0 g, 100%) as a pale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.14 (3H, t, J=7.4), 1.44(3H, t, J=6.9), 1.64-1.80 (2H, m), 2.38 (2H, q, J=7.3), 2.62-2.72 (2H,m), 3.97 (2H, s), 4.07 (2H, q, J=6.9), 6.95-7.04 (2H, m), 7.08-7.16 (2H,m), 7.36-7.51 (6H, m), 7.57-7.66 (1H, m), 7.74 (1H, dd, J=7.7, 0.94)

125b)2-ethyl-3-(4-ethoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (5.8 g), sodium hydrogencarbonate (8.5 g) and dimethyl sulfoxide (30 mL) was stirred at 50° C.for 30 min,4′-{[2-ethyl-1-(4-ethoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(4.0 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (2.0 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.9 mL) were added, and themixture was stirred at room temperature for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (2.1 g, 46%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3), 1.04 (3H, t, J=7.3),1.36 (3H, t, J=6.9), 1.49-1.65 (2H, m), 2.28 (2H, q, J=7.3), 2.46-2.58(2H, m), 3.87 (2H, s), 4.08 (2H, q, J=6.9), 6.99-7.09 (2H, m), 7.18-7.32(6H, m), 7.48-7.58 (2H, m), 7.61-7.74 (2H, m), 12.40 (1H, s)

Example 1266-butyl-2-ethyl-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

126a)4′-{[4-butyl-2-ethyl-1-(4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.0 g), 4-methoxyphenylboronic acid (1.6 g), copper(II) acetate (2.0g), pyridine (2.2 mL), triethylamine (3.8 mL), molecular sieves 4 A (4.0g) and dichloromethane (40 mL) was stirred for 6 days. The reactionmixture was diluted with ethyl acetate, and the insoluble material wasfiltered off. The filtrate was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography to give thetitle compound (2.6 g, 100%) as a colorless liquid.

¹H NMR (300 MHz, CDCl₃) δ 0.95 (3H, t, J=7.2), 1.15 (3H, t, J=7.4),1.34-1.53 (2H, m), 1.56-1.72 (2H, m), 2.38 (2H, q, J=7.4), 2.64-2.73(2H, m), 3.85 (3H, s), 3.96 (2H, s), 6.98-7.18 (4H, m), 7.36-7.51 (6H,m), 7.57-7.67 (1H, m), 7.74 (1H, dd, J=7.7, 1.3)

126b)6-butyl-2-ethyl-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (3.8 g), sodium hydrogencarbonate (5.4 g) and dimethyl sulfoxide (26 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-2-ethyl-1-(4-methoxyphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.6 g) was added, and the mixture was stirred at 90° C. overnight. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (26 mL), N,N′-carbonyldiimidazole (1.3 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.2 mL) were added, and themixture was stirred at room temperature for 30 min. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (2.0 g, 70%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.04 (3H, t, J=7.3),1.26-1.40 (2H, m), 1.45-1.59 (2H, m), 2.28 (2H, q, J=7.3), 2.47-2.60(2H, m), 3.82 (3H, s), 3.86 (2H, s), 7.03-7.10 (2H, m), 7.19-7.32 (6H,m), 7.47-7.59 (2H, m), 7.62-7.73 (2H, m), 12.41 (1H, s)

Example 1273-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

127a)4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.50 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.52g), copper(II) acetate (0.49 g), pyridine (0.55 mL), triethylamine (0.94mL), molecular sieves 4 A (1.0 g) and dichloromethane (5 mL) was stirredfor 2 days. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off. The filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound (0.54 g, 80%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.16 (3H, t, J=7.3), 1.48(3H, s), 1.52 (3H, s), 1.64-1.80 (2H, m), 2.41 (2H, q, J=7.3), 2.63-2.71(2H, m), 3.06 (2H, s), 3.96 (2H, s), 6.77-7.01 (3H, m), 7.37-7.52 (6H,m), 7.62 (1H, t, J=7.7), 7.74 (1H, d, J=7.7)

127b)3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.75 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C.for 30 min,4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.26 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.40 g, 66%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3), 1.01-1.13 (3H, m), 1.44(3H, s), 1.46 (3H, s), 1.50-1.65 (2H, m), 2.31 (2H, q, J=7.3), 2.47-2.57(2H, m), 3.05 (2H, s), 3.86 (2H, s), 6.80 (1H, d, J=8.4), 7.02 (1H, dd,J=8.4, 2.3), 7.14 (1H, d, J=2.0), 7.18-7.32 (4H, m), 7.46-7.59 (2H, m),7.63-7.72 (2H, m), 12.38 (1H, s)

Example 128

6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.75 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-{[4-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), thiocarbonyldiimidazole (0.21 g)was added, and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), boron trifluoride-diethyl ethercomplex (0.71 mL) was added at 0° C., and the mixture was stirred for 1hr. The reaction mixture was diluted with ethyl acetate, washed withsaturated aqueous potassium hydrogen sulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound (0.086 g,32%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.89 (3H, m), 1.22-1.38 (2H, m),1.39-1.54 (8H, m), 2.08 (3H, s), 2.45-2.54 (2H, m), 3.05 (2H, s), 3.84(2H, s), 6.80 (1H, d, J=8.4), 7.04 (1H, dd, J=8.4, 2.2), 7.12-7.27 (5H,m), 7.44-7.53 (2H, m), 7.56-7.66 (2H, m), 12.86 (1H, s)

6-Butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 129

3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), thiocarbonyldiimidazole (0.43 g)was added, and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), boron trifluoride-diethyl ethercomplex (1.2 mL) was added at 0° C., and the mixture was stirred for 1hr. The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound (0.30 g, 27%) as acolorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3), 1.30 (6H, d, J=6.0),1.45-1.63 (2H, m), 2.06 (3H, s), 2.44-2.54 (2H, m), 3.85 (2H, s),4.60-4.74 (1H, m), 6.98-7.06 (2H, m), 7.11-7.19 (2H, m), 7.20-7.28 (4H,m), 7.44-7.53 (2H, m), 7.55-7.67 (2H, m), 12.85 (1H, s)

Example 130

3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-thiadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), thiocarbonyldiimidazole (0.43 g)was added, and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), boron trifluoride-diethyl ethercomplex (1.2 mL) was added at 0° C., and the mixture was stirred for 1hr. The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound (0.31 g, 28%) as acolorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.2), 1.41-1.61 (8H, m), 2.08(3H, s), 2.45-2.53 (4H, m), 3.84 (2H, s), 6.80 (1H, d, J=8.3), 7.04 (1H,dd, J=8.3, 2.3), 7.11-7.19 (3H, m), 7.21-7.27 (2H, m), 7.44-7.53 (2H,m), 7.56-7.66 (2H, m), 12.85 (1H, s)

Example 131

3-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.50 g), (2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronic acid (0.30g), copper(II) acetate (0.27 g), pyridine (0.59 mL), triethylamine (1.0mL), molecular sieves 4 A (1.0 g) and dichloromethane (5 mL) was stirredfor 3 days. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off. The filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography. The resulting crudely purified product was added to amixture of hydroxylammonium chloride (0.97 g), sodium hydrogen carbonate(1.4 g) and dimethyl sulfoxide (7 mL), and the mixture was stirred at90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (7 mL),N,N′-carbonyldiimidazole (0.34 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, and the mixturewas stirred at room temperature for 1 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.66 g, 80%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.1), 1.30 (3H, s), 1.32 (3H,s), 1.46-1.62 (2H, m), 1.79 (2H, t, J=6.6), 2.07 (3H, s), 2.45-2.55 (2H,m), 2.76 (2H, t, J=6.4), 3.85 (2H, s), 6.81 (1H, d, J=8.7), 6.98-7.09(2H, m), 7.18-7.30 (4H, m), 7.48-7.58 (2H, m), 7.62-7.73 (2H, m), 12.36(1H, s)

3-(2,2-Dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 132

6-butyl-3-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.50 g), (2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronic acid (0.30g), copper(II) acetate (0.27 g), pyridine (0.59 mL), triethylamine (1.0mL), molecular sieves 4 A (1.0 g) and dichloromethane (5 mL) was stirredfor 3 days. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off. The filtrate was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography. The resulting crudely purified product was added to amixture of hydroxylammonium chloride (0.97 g), sodium hydrogen carbonate(1.4 g) and dimethyl sulfoxide (7 mL), and the mixture was stirred at90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (7 mL),N,N′-carbonyldiimidazole (0.34 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, and the mixturewas stirred at room temperature for 1 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.64 g, 80%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.89 (3H, m), 1.23-1.38 (8H, m),1.41-1.55 (2H, m), 1.79 (2H, t, J=6.5), 2.07 (3H, s), 2.45-2.57 (2H, m),2.76 (2H, t, J=6.5), 3.85 (2H, s), 6.81 (1H, d, J=8.6), 6.98-7.10 (2H,m), 7.18-7.31 (4H, m), 7.47-7.58 (2H, m), 7.62-7.72 (2H, m), 12.39 (1H,s)

Example 1336-propyl-3-[4-(2-fluoroethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

133a)4′-({1-[4-(2-fluoroethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), potassium carbonate (0.48 g) and 1-bromo-2-fluoroethane (0.25mL) in N,N-dimethylformamide (10 mL) was stirred at 100° C. overnight.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound (1.1 g, 100%) as apale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.59-1.77 (2H, m), 2.17(3H, s), 2.61-2.70 (2H, m), 3.97 (2H, s), 4.18-4.23 (1H, m), 4.27-4.33(1H, m), 4.67-4.72 (1H, m), 4.82-4.88 (1H, m), 7.02-7.09 (2H, m),7.12-7.19 (2H, m), 7.37-7.51 (6H, m), 7.58-7.65 (1H, m), 7.74 (1H, d,J=7.5)

133b)6-propyl-3-[4-(2-fluoroethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (11 mL) was stirred at 50° C.for 30 min,4′-({1-[4-(2-fluoroethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.1 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (11 mL), N,N′-carbonyldiimidazole (0.56 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (1.1 g, 88%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3), 1.47-1.62 (2H, m), 2.07(3H, s), 2.43-2.59 (2H, m), 3.87 (2H, s), 4.22-4.29 (1H, m), 4.33-4.38(1H, m), 4.69 (1H, dd, J=4.6, 2.9), 4.83-4.88 (1H, m), 7.05-7.14 (2H,m), 7.18-7.34 (6H, m), 7.46-7.60 (2H, m), 7.62-7.73 (2H, m), 12.38 (1H,s)

Example 1343-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

134a)4′-{[1-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.72 g), (2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronic acid (0.82g), copper(II) acetate (0.73 g), pyridine (0.81 mL), triethylamine (1.4mL), molecular sieves 4 A (1.5 g) and dichloromethane (10 mL) wasstirred for 16 hr. The reaction mixture was diluted with ethyl acetate,and the insoluble material was filtered off. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound (0.73 g,70%) as a pale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.3), 1.33 (3H, s), 1.37 (3H,s), 1.60-1.75 (2H, m), 1.82 (2H, t, J=6.8), 2.19 (3H, s), 2.56-2.68 (2H,m), 2.68-2.92 (2H, m), 3.98 (2H, s), 6.83-6.94 (3H, m), 7.17-7.28 (2H,m), 7.37-7.50 (3H, m), 7.58-7.67 (1H, m), 7.74 (1H, d, J=7.9)

134b)3-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (7 mL) was stirred at 50° C.for 30 min,4′-{[1-(2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.73 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (7 mL), N,N′-carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.42 g, 52%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.3), 1.30 (3H, s), 1.32 (3H,s), 1.48-1.63 (2H, m), 1.79 (2H, t, J=6.5), 2.08 (3H, s), 2.44-2.54 (2H,m), 2.75 (2H, t, J=6.5), 3.85 (2H, s), 6.80 (1H, d, J=8.4), 6.97-7.22(5H, m), 7.51-7.62 (2H, m), 7.64-7.74 (2H, m), 12.45 (1H, s)

Example 1353-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

135a)4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.72 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.77g), copper(II) acetate (0.73 g), pyridine (0.81 mL), triethylamine (1.4mL), molecular sieves 4 A (1.5 g) and dichloromethane (10 mL) wasstirred for 16 hr. The reaction mixture was diluted with ethyl acetate,and the insoluble material was filtered off. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound (0.71 g,70%) as a pale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.38), 1.48 (3H, s), 1.52 (3H,s), 1.60-1.76 (2H, m), 2.21 (3H, s), 2.59-2.69 (2H, m), 3.05 (2H, s),3.98 (2H, s), 6.76-6.84 (1H, m), 6.88-6.99 (2H, m), 7.22 (2H, d, J=9.0),7.38-7.50 (3H, m), 7.63 (1H, t, J=7.0), 7.75 (1H, d, J=7.9)

135b)3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogencarbonate (1.4 g) and dimethyl sulfoxide (7 mL) was stirred at 50° C.for 30 min,4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.71 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (7 mL), N,N′-carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.55 g, 70%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3), 1.43 (3H, s), 1.45 (3H,s), 1.49-1.64 (2H, m), 2.09 (3H, s), 2.40-2.56 (2H, m), 3.05 (2H, s),3.85 (2H, s), 6.80 (1H, d, J=8.2), 6.98-7.07 (2H, m), 7.10-7.23 (3H, m),7.51-7.62 (2H, m), 7.65-7.74 (2H, m), 12.45 (1H, s)

Example 1363-(4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

136a)4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.2g), copper(II) acetate (1.1 g), pyridine (1.2 mL), triethylamine (2.1mL), molecular sieves 4 A (2.0 g) and dichloromethane (10 mL) wasstirred for 3 days. The reaction mixture was diluted with ethyl acetate,and the insoluble material was filtered off. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound (1.4 g,100%) as a pale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.33-1.47 (2H, m), 1.48(6H, s), 1.60-1.73 (2H, m), 2.47-2.55 (2H, m), 3.04 (2H, s), 4.95 (2H,s), 6.76 (1H, d, J=8.6), 7.39-7.52 (4H, m), 7.52-7.58 (2H, m), 7.60-7.69(2H, m), 7.71-7.80 (2H, m)

136b)3-(4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

A mixture of hydroxylammonium chloride (2.1 g), sodium hydrogencarbonate (3.0 g) and dimethyl sulfoxide (10 mL) was stirred at 50° C.for 30 min,4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile(1.4 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.73 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.67 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.59 g, 38%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.1), 1.24-1.39 (2H, m), 1.42(6H, s), 1.46-1.59 (2H, m), 2.47-2.57 (2H, m), 3.05 (2H, s), 4.95 (2H,s), 6.76 (1H, d, J=8.7), 7.29-7.37 (4H, m), 7.49-7.61 (3H, m), 7.65-7.74(3H, m), 12.40 (1H, s)

3-(4′-{[3-Butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    sodium salt-   3-(4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    potassium salt-   3-(4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    0.5 calcium salt-   3-(4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    hydrochloride-   3-(4′-{[3-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one    hydrobromide

Example 137

N-(2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4-yl)pentane-1-sulfonamide

A solution of4′-[(4-chloro-2-methyl-6-propylpyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.72 g), pentane-1-sulfonamide (0.61 g) and potassium carbonate (0.55g) in N,N-dimethylacetamide (10 mL) was stirred at 150° C. overnight.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. A mixture of the residue,hydroxylammonium chloride (1.4 g), sodium hydrogen carbonate (2.0 g) anddimethyl sulfoxide (10 mL) was stirred at 90° C. overnight. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.49 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.40 g, 38%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.76-0.90 (6H, m), 1.13-1.67 (8H, m), 2.40(3H, s), 2.47-2.59 (2H, m), 3.13 (2H, br s), 3.92 (2H, s), 7.17-7.34(4H, m), 7.46-7.59 (2H, m), 7.62-7.73 (2H, m), 12.39 (1H, s), 12.64 (1H,s)

Example 138

N-(2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4-yl)benzenesulfonamide

A solution of4′-[(4-chloro-2-methyl-6-propylpyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.72 g), benzenesulfonamide (0.63 g) and potassium carbonate (0.55 g)in N,N-dimethylacetamide (10 mL) was stirred at 150° C. overnight. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. A mixture of the residue, hydroxylammonium chloride(1.4 g), sodium hydrogen carbonate (2.0 g) and dimethyl sulfoxide (10mL) was stirred at 90° C. overnight. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (10 mL),N,N′-carbonyldiimidazole (0.49 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.87 g, 80%) as a whitesolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.2), 1.29-1.45 (2H, m), 2.28(3H, s), 2.47-2.56 (2H, m), 3.92 (2H, s), 7.16-7.32 (4H, m), 7.39-7.60(5H, m), 7.62-7.73 (2H, m), 7.79-7.87 (2H, m), 12.25-12.96 (2H, m)

Example 1393-[4-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

139a)4′-({1-[4-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

4′-{[1-(4-Acetylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.2 g) was dissolved in tetrahydrofuran (12 mL), methylmagnesiumbromide (1.0 M tetrahydrofuran solution, 6.4 mL) was added at −78° C.,and the mixture was stirred for 1 hr. A 5% aqueous potassium hydrogensulfate solution was added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound (0.45 g,35%) as a pale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.59 (6H, s), 1.63-1.77(2H, m), 2.17 (3H, s), 2.62-2.70 (2H, m), 3.97 (2H, s), 7.20 (2H, d,J=8.3), 7.37-7.51 (6H, m), 7.57-7.68 (3H, m), 7.74 (1H, d, J=7.9)

139b)3-[4-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.65 g), sodium hydrogencarbonate (0.95 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-({1-[4-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.45 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.15 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.27 g, 54%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.1), 1.43-1.62 (8H, m), 2.05(3H, s), 2.46-2.57 (2H, m), 3.86 (2H, s), 5.13 (1H, s), 7.18-7.31 (6H,m), 7.47-7.73 (6H, m), 12.36 (1H, s)

Example 1403-(4-fluorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

140a)4′-{[1-(4-fluorophenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 4-fluorophenylboronic acid (0.82 g), copper(II) acetate (1.1g), pyridine (1.2 mL), triethylamine (2.0 mL), molecular sieves 4 A (2.0g) and dichloromethane (10 mL) was stirred for 4 days. The reactionmixture was diluted with ethyl acetate, and the insoluble material wasfiltered off. The filtrate was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography to give thetitle compound (0.47 g, 37%) as a colorless liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.62-1.77 (2H, m), 2.17(3H, s), 2.61-2.70 (2H, m), 3.96 (2H, s), 7.18-7.27 (4H, m), 7.36-7.51(6H, m), 7.58-7.66 (1H, m), 7.74 (1H, d, J=7.5)

140b)3-(4-fluorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.74 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-{[1-(4-fluorophenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.47 g) was added, and the mixture was stirred at 90° C. overnight. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.26 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.49 g, 91%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3), 1.47-1.63 (2H, m), 2.06(3H, s), 2.46-2.56 (2H, m), 3.87 (2H, s), 7.18-7.32 (4H, m), 7.32-7.43(2H, m), 7.42-7.59 (4H, m), 7.62-7.72 (2H, m), 12.37 (1H, s)

Example 1415-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one

141a)3′-fluoro-4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 4-isopropoxyphenylboronic acid (1.1 g), copper(II) acetate (1.1g), pyridine (1.2 mL), triethylamine (2.0 mL), molecular sieves 4 A (2.0g) and dichloromethane (10 mL) was stirred for 4 days. The reactionmixture was diluted with ethyl acetate, and the insoluble material wasfiltered off. The filtrate was concentrated under reduced pressure, andthe residue was purified by silica gel column chromatography to give thetitle compound (0.56 g, 42%) as a colorless liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.3), 1.36 (6H, d, J=6.0),1.59-1.75 (2H, m), 2.19 (3H, s), 2.60-2.69 (2H, m), 3.98 (2H, s),4.50-4.64 (1H, m), 6.95-7.02 (2H, m), 7.08-7.14 (2H, m), 7.18-7.25 (2H,m), 7.39-7.49 (3H, m), 7.59-7.67 (1H, m), 7.75 (1H, dd, J=7.6, 0.85)

141b)5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.85 g), sodium hydrogencarbonate (1.2 g) and dimethyl sulfoxide (6 mL) was stirred at 50° C.for 30 min,3′-fluoro-4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.56 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (6 mL), N,N′-carbonyldiimidazole (0.30 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.51 g, 70%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3), 1.29 (6H, d, J=6.0),1.47-1.63 (2H, m), 2.08 (3H, s), 2.43-2.54 (2H, m), 3.85 (2H, s),4.60-4.74 (1H, m), 6.97-7.06 (3H, m), 7.09-7.28 (4H, m), 7.30-7.60 (2H,m), 7.64-7.74 (2H, m), 12.43 (1H, s)

5-{[3-Fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one    sodium salt-   5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one    potassium salt-   5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one    hydrochloride-   5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 1423-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

142a) (2,2-dimethyl-2H-chromen-6-yl)boronic acid

To a solution of 6-bromo-2,2-dimethyl-2H-chromene (18 g) intetrahydrofuran (150 mL) was added butyllithium (53 mL, 1.6 M hexanesolution) at −78° C. under an argon atmosphere, and the mixture wasstirred for 30 min. Triisopropyl borate (21 mL) was added, and themixture was stirred for 3 hr while allowing to warm to room temperature.1 M hydrochloric acid (150 mL) was added to the reaction mixture, andthe mixture was stirred for 2 hr and extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was evaporated. The residue waspurified by silica gel column chromatography to give the title compound(13 g, 82%) as colorless crystals.

¹H NMR (300 MHz, DMSO-d₆) δ 1.37 (3H, s), 1.37 (3H, s), 5.67-5.75 (1H,m), 6.33-6.52 (1H, m), 6.64-6.75 (1H, m), 7.43-7.65 (2H, m)

142b)4′-{[1-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(21 g), (2,2-dimethyl-2H-chromen-6-yl)boronic acid (12 g), copper(II)acetate (11 g), pyridine (24 mL), triethylamine (42 mL), molecularsieves 4 A (40 g) and dichloromethane (200 mL) was stirred for 4 days.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off. The filtrate was concentrated under reducedpressure, and the residue was purified by silica gel columnchromatography to give the title compound (15 g, 51%) as a colorlesssolid.

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.3), 1.43 (3H, s), 1.48 (3H,s), 1.61-1.75 (2H, m), 2.20 (3H, s), 2.59-2.69 (2H, m), 3.96 (2H, s),5.65 (1H, d, J=9.8), 6.28 (1H, d, J=9.8), 6.80-6.97 (3H, m), 7.36-7.51(6H, m), 7.60 (1H, d, J=7.5), 7.74 (1H, d, J=7.9)

142c)3-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.70 g), sodium hydrogencarbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-{[1-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.56 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.42 g, 74%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.3), 1.41 (3H, s), 1.42 (3H,s), 1.46-1.62 (2H, m), 2.09 (3H, s), 2.48-2.54 (2H, m), 3.86 (2H, s),5.83 (1H, d, J=9.9), 6.41 (1H, d, J=9.9), 6.85 (1H, d, J=9.4), 7.06-7.12(2H, m), 7.18-7.30 (4H, m), 7.48-7.58 (2H, m), 7.62-7.72 (2H, m), 12.38(1H, s)

3-(2,2-Dimethyl-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-(2,2-dimethyl-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 1433-(4-methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

143a) (2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)boronic acid

A solution of 6-bromo-2,2-dimethyl-2,3-dihydro-4H-chromen-4-one (21 g),pinacol diborane (25 g), palladium acetate (0.92 g) and potassiumacetate (2.4 g) in N,N-dimethylformamide (250 mL) was stirred at 90° C.for 2 hr under an argon atmosphere. Water was added to the reactionmixture, and the mixture was extracted with diethyl ether. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was dissolved in tetrahydrofuran (80 mL), and 0.5 Mhydrochloric acid (40 mL) and sodium periodate (7.0 g) were added at 0°C. The reaction mixture was stirred at room temperature for 2 hr andextracted with ethyl acetate. The organic layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was crystallized fromethyl acetate and hexane to give the title compound (15 g, 84%) as acolorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.39 (6H, s), 2.79 (2H, s), 6.93 (1H, d,J=8.3), 7.93 (1H, dd, J=8.3, 1.7), 8.06 (2H, s), 8.24 (1H, d, J=1.7)

143b)4′-{[1-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(10 g), (2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)boronic acid(6.6 g), copper(II) acetate (5.5 g), pyridine (12 mL), triethylamine (21mL), molecular sieves 4 A (20 g) and dichloromethane (100 mL) wasstirred for 3 days. The reaction mixture was diluted with ethyl acetate,and the insoluble material was filtered off. The filtrate wasconcentrated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound (7.0 g, 45%)as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.3), 1.49 (3H, s), 1.50 (3H,s), 1.62-1.76 (2H, m), 2.18 (3H, s), 2.65 (2H, dd, J=9.0, 6.4), 2.75(2H, s), 3.96 (2H, s), 7.08 (1H, d, J=9.0), 7.30-7.51 (7H, m), 7.58-7.65(1H, m), 7.69-7.76 (2H, m)

143c)4′-{[1-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

4′-{[1-(2,2-Dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(7.0 g) was dissolved in methanol (35 mL) and tetrahydrofuran (35 mL),and sodium borohydride (0.61 g) was added at 0° C. After stirring for 30min, 5% aqueous potassium hydrogen sulfate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (7.0 g, 100%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.95-1.05 (3H, m), 1.44 (3H, s), 1.61-1.74(2H, m), 1.76 (3H, s), 1.78-1.91 (1H, m), 2.09-2.23 (4H, m), 2.57-2.69(2H, m), 3.88-4.01 (2H, m), 4.74-4.88 (1H, m), 6.84-6.90 (1H, m),6.92-7.03 (1H, m), 7.24-7.51 (7H, m), 7.61 (1H, t, J=7.5), 7.73 (1H, d,J=7.5)

143d)4′-{[1-(4-methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.52 g) in N,N-dimethylformamide (5 mL) were added sodium hydride(0.080 g) and iodomethane (0.13 mL), and the mixture was stirred for 1hr. A 5% aqueous potassium hydrogen sulfate solution was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.41 g, 77%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.1), 1.29-1.50 (6H, m), 1.68(2H, d, J=7.5), 1.83-2.22 (5H, m), 2.58-2.69 (2H, m), 3.44 (3H, s),3.89-4.04 (2H, m), 4.40-4.50 (1H, m), 6.86-6.92 (1H, m), 6.96-7.04 (1H,m), 7.22-7.30 (1H, m), 7.36-7.51 (6H, m), 7.61 (1H, t, J=7.5), 7.74 (1H,d, J=7.5)

143e)3-(4-methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.53 g), sodium hydrogencarbonate (0.77 g) and dimethyl sulfoxide (4 mL) was stirred at 50° C.for 30 min,4′-{[1-(4-methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.41 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (4 mL), N,N′-carbonyldiimidazole (0.19 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.35 g, 77%) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.4), 1.32 (3H, d, J=3.0),1.40 (3H, d, J=3.0), 1.47-1.63 (2H, m), 1.80-1.95 (1H, m), 2.07 (3H, d,J=4.7), 2.12-2.26 (1H, m), 2.46-2.56 (2H, m), 3.39 (3H, d, J=3.7), 3.86(2H, s), 4.38-4.50 (1H, m), 6.86 (1H, dd, J=8.6, 3.0), 7.09-7.18 (1H,m), 7.18-7.32 (5H, m), 7.48-7.58 (2H, m), 7.61-7.73 (2H, m), 12.38 (1H,s)

Example 1443-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

144a)4′-[(1-{2,2-dimethyl-4-[(triisopropylsilyl)oxy]-3,4-dihydro-2H-chromen-6-yl}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(3.1 g) and 2,6-lutidine (2.1 mL) in dichloromethane (30 mL) was addedtriisopropylsilyl trifluoromethanesulfonate (3.2 mL), and the mixturewas stirred for 1 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(4.1 g, 100%) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 0.96-1.49 (30H, m), 1.60-1.80 (2H, m),1.88-2.00 (1H, m), 2.07-2.16 (1H, m), 2.16-2.21 (3H, m), 2.55-2.75 (2H,m), 3.85-4.08 (2H, m), 5.05 (1H, s), 6.84-6.92 (1H, m), 6.95-7.02 (1H,m), 7.23 (1H, d, J=2.2), 7.36-7.51 (6H, m), 7.57-7.65 (1H, m), 7.74 (1H,dd, J=7.8, 1.04)

144b)3-{2,2-dimethyl-4-[(triisopropylsilyl)oxy]-3,4-dihydro-2H-chromen-6-yl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (4.2 g), sodium hydrogencarbonate (6.1 g) and dimethyl sulfoxide (40 mL) was stirred at 50° C.for 30 min,4′-[(1-{2,2-dimethyl-4-[(triisopropylsilyl)oxy]-3,4-dihydro-2H-chromen-6-yl}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(4.1 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (1.5 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.3 mL) were added, and themixture was stirred at room temperature for 30 min. The reaction mixturewas diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (4.4 g, 100%) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 0.98-1.51 (30H, m), 1.65-1.85 (2H, m),1.85-1.99 (1H, m), 2.05-2.15 (1H, m), 2.17 (3H, s), 2.57-2.78 (2H, m),3.78-4.04 (2H, m), 4.94-5.08 (1H, m), 6.81-6.98 (2H, m), 7.16-7.25 (3H,m), 7.28-7.36 (2H, m), 7.37-7.51 (2H, m), 7.53-7.63 (1H, m), 7.80 (1H,d, J=7.7)

144c)3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-{2,2-dimethyl-4-[(triisopropylsilyl)oxy]-3,4-dihydro-2H-chromen-6-yl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(4.0 g) in tetrahydrofuran (20 mL) was added tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 8.2 mL), and the mixture was stirredfor 2 hr. The reaction mixture was diluted with ethyl acetate, washedwith 5% aqueous potassium hydrogen sulfate solution and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound (3.0 g, 95%)as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.3), 1.28 (3H, s), 1.40 (3H,s), 1.47-1.64 (2H, m), 1.67-1.82 (1H, m), 2.05-2.17 (4H, m), 2.45-2.55(2H, m), 3.87 (2H, s), 4.65-4.77 (1H, m), 5.44 (1H, dd, J=6.0, 1.3),6.82 (1H, d, J=8.6), 7.05-7.14 (1H, m), 7.18-7.34 (5H, m), 7.48-7.59(2H, m), 7.62-7.73 (2H, m), 12.38 (1H, s)

3-(4-Hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 145

3-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A solution of3-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.40 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.44 g) in dichloromethane (4 mL) was stirred for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueoussodium hydrogen carbonate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.34 g, 86%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.4), 1.43 (3H, s), 1.45 (3H,s), 1.47-1.63 (2H, m), 2.07 (3H, s), 2.46-2.55 (2H, m), 2.87 (2H, s),3.86 (2H, s), 7.14 (1H, d, J=8.7), 7.18-7.31 (4H, m), 7.48-7.60 (3H, m),7.62-7.73 (3H, m), 12.38 (1H, s)

3-(2,2-Dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 146

N-{2,2-dimethyl-6-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]-3,4-dihydro-2H-chromen-4-yl}acetamide

3-(4-Hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(1.0 g) was dissolved in acetonitrile (10 mL), and concentratedhydrochloric acid (1.0 mL) was added dropwise at 0° C. The reactionmixture was stirred at room temperature for 30 min. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous sodiumhydrogen carbonate solution and then with saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.82 g, 76%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.84-0.94 (3H, m), 1.29 (3H, s), 1.41 (3H,s), 1.46-1.62 (2H, m), 1.66-1.79 (1H, m), 1.89 (3H, d, J=7.5), 1.97-2.11(4H, m), 2.44-2.55 (2H, m), 3.85 (2H, s), 5.02-5.19 (1H, m), 6.85 (1H,dd, J=8.4, 1.70), 7.05-7.14 (2H, m), 7.18-7.31 (4H, m), 7.47-7.58 (2H,m), 7.61-7.73 (2H, m), 8.15-8.40 (1H, m), 12.38 (1H, s)

Example 147

3-(4-amino-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

N-{2,2-Dimethyl-6-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]-3,4-dihydro-2H-chromen-4-yl}acetamide(0.30 g) was dissolved in 6 M hydrochloric acid (1 mL) and 1,4-dioxane(2 mL), and the mixture was stirred at 90° C. for 2 days. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueoussodium hydrogen carbonate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound (0.25 g, 90%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-0.97 (3H, m), 1.26 (3H, d, J=6.0), 1.44(3H, s), 1.52-1.84 (3H, m), 2.06-2.11 (3H, m), 2.14-2.25 (1H, m),2.47-2.63 (2H, m), 3.74-3.91 (2H, m), 4.34-4.44 (1H, m), 6.90 (1H, dd,J=8.6, 1.3), 7.15-7.26 (5H, m), 7.32-7.44 (3H, m), 7.44-7.54 (3H, m)

Example 1486-ethyl-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

148a)4′-{[4-ethyl-5-(4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

4′-[(5-Bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.50 g), 4-isopropoxyphenylboronic acid (0.31 g) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.050 g) weredissolved in 2 M aqueous cesium carbonate solution (2 mL) and1,4-dioxane (10 mL), and the mixture was stirred at 90° C. overnightunder an argon atmosphere. The reaction mixture was diluted with ethylacetate, and the insoluble material was filtered off through celite. Thefiltrate was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.50 g, 89%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.4), 1.18 (3H, t, J=7.4), 1.35(3H, d, J=6.0), 1.36 (3H, s), 1.74-1.89 (2H, m), 2.49 (2H, q, J=7.4),2.68-2.77 (2H, m), 4.50-4.64 (1H, m), 5.37 (2H, s), 6.93 (2H, d,J=8.67), 7.22 (2H, d, J=8.8), 7.36 (2H, d, J=8.4), 7.41-7.56 (4H, m),7.60-7.68 (1H, m), 7.76 (1H, dd, J=7.7, 0.94)

148b)6-ethyl-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogencarbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-{[4-ethyl-5-(4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.50 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.44 g, 79%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3), 1.10 (3H, t, J=7.4),1.29 (3H, d, J=6.0), 1.58-1.73 (2H, m), 2.37 (2H, q, J=7.4), 2.68 (2H,t, J=7.4), 4.57-4.70 (1H, m), 5.34 (2H, s), 6.90-6.97 (2H, m), 7.14-7.21(2H, m), 7.23-7.35 (4H, m), 7.49-7.61 (2H, m), 7.63-7.74 (2H, m), 12.39(1H, s)

Example 1492-butyl-5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

149a)4-{[2-butyl-5-(4-isopropoxyphenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

4′-[(5-Bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.50 g), 4-isopropoxyphenylboronic acid (0.31 g) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.050 g) weredissolved in 2 M aqueous cesium carbonate solution (2 mL) and1,4-dioxane (10 mL), and the mixture was stirred at 90° C. overnightunder an argon atmosphere. The reaction mixture was diluted with ethylacetate, and the insoluble material was filtered off through celite. Thefiltrate was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.56 g, 99%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3), 1.32-1.49 (2H, m), 1.35(3H, d, J=6.0), 1.66-1.79 (2H, m), 2.24 (3H, s), 2.69-2.78 (2H, m),4.50-4.65 (1H, m), 5.38 (2H, s), 6.89-6.97 (2H, m), 7.21-7.29 (2H, m),7.35 (2H, d, J=8.4), 7.40-7.56 (4H, m), 7.60-7.68 (1H, m), 7.76 (1H, dd,J=7.8, 0.85)

149b)2-butyl-5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.79 g), sodium hydrogencarbonate (1.2 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-{[2-butyl-5-(4-isopropoxyphenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.56 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.28 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.49 g, 78%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.5), 1.21-1.38 (8H, m),1.51-1.65 (2H, m), 2.13 (3H, s), 2.63-2.73 (2H, m), 4.56-4.72 (1H, m),5.35 (2H, s), 6.89-6.97 (2H, m), 7.16-7.36 (6H, m), 7.48-7.61 (2H, m),7.63-7.74 (2H, m), 12.40 (1H, s)

Example 1502-ethoxy-5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

150a)4′-{[2-ethoxy-5-(4-isopropoxyphenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

4′-[(5-Bromo-2-ethoxy-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.50 g), 4-isopropoxyphenylboronic acid (0.32 g) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.050 g) weredissolved in 2 M aqueous cesium carbonate solution (2 mL) and1,4-dioxane (10 mL), and the mixture was stirred at 90° C. overnightunder an argon atmosphere. The reaction mixture was diluted with ethylacetate, and the insoluble material was filtered off through celite. Thefiltrate was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.53 g, 94%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.35 (3H, d, J=6.0), 1.42 (3H, t, J=7.0), 2.13(3H, s), 4.43-4.62 (3H, m), 5.25 (2H, s), 6.87-6.96 (2H, m), 7.16-7.23(2H, m), 7.39-7.52 (4H, m), 7.54-7.67 (3H, m), 7.75 (1H, dd, J=7.7,0.94)

150b)2-ethoxy-5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.77 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (5 mL) was stirred at 50° C.for 30 min,4′-{[2-ethoxy-5-(4-isopropoxyphenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.53 g) was added, and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 30 min. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.39 g, 66%) as a colorlesssolid.

¹H NMR (300 MHz, DMSO-d₆) δ 1.24-1.32 (9H, m), 2.07 (3H, s), 4.40 (2H,q, J=7.2), 4.56-4.71 (1H, m), 5.13 (2H, s), 6.92 (2H, d, J=8.8), 7.16(2H, d, J=8.8), 7.26-7.39 (4H, m), 7.49-7.60 (2H, m), 7.64-7.73 (2H, m),12.39 (1H, s)

Example 1516-butyl-3-[(3,5-dimethylisoxazol-4-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

151a)4′-({4-butyl-1-[(3,5-dimethylisoxazol-4-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.02 g), potassium carbonate (1.28 g),4-(chloromethyl)-3,5-dimethylisoxazole (0.45 g) andN,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless viscous substance (0.43 g, 33%).

¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, J=7.4, 3H), 1.31-1.44 (m, 2H),1.53-1.64 (m, 2H), 2.10 (s, 3H), 2.21 (s, 3H), 2.43 (s, 3H), 2.58-2.67(m, 2H), 3.98 (s, 2H), 5.06 (s, 2H), 7.33-7.37 (m, 2H), 7.38-7.50 (m,4H), 7.62 (td, J=7.7, 1.2, 1H), 7.74 (dd, J=7.7, 1.3, 1H)

151b)6-butyl-3-[(3,5-dimethylisoxazol-4-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.57 g), sodium hydrogencarbonate (0.78 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[(3,5-dimethylisoxazol-4-yl)methyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.43 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.20 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.26 g,55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.3, 3H), 1.04 (d, J=6.0, 3H),1.22-1.34 (m, 2H), 1.40-1.52 (m, 2H), 2.17 (s, 3H), 2.42 (s, 3H),2.48-2.52 (m, 2H), 3.88 (s, 2H), 5.08 (s, 2H), 7.18-7.26 (m, 4H),7.47-7.53 (m, 1H), 7.56 (dd, J=7.4, 1.13, 1H), 7.63-7.72 (m, 2H), 12.39(s, 1H)

Example 1526-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-one

152a)4′-({4-butyl-2-methyl-6-oxo-1-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.24 g), potassium carbonate (0.94 g),3-(chloromethyl)-5-phenyl-1,2,4-oxadiazole (0.68 g) andN,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless viscous substance (0.79 g, 45%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.4, 3H), 1.31-1.44 (m, 2H),1.52-1.65 (m, 2H), 2.57-2.64 (m, 5H), 4.00 (s, 2H), 5.45 (s, 2H),7.31-7.49 (m, 8H), 7.50-7.59 (m, 2H), 7.68 (dd, J=7.7, 0.9, 1H),8.02-8.07 (m, 2H)

152b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-6-oxo-1-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.79 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.37 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.61 g,69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.3, 3H), 1.24-1.38 (m, 2H),1.40-1.53 (m, 2H), 2.46-2.55 (m, 2H), 2.57 (s, 3H), 3.87 (s, 2H), 5.47(s, 2H), 7.17-7.26 (m, 4H), 7.46-7.57 (m, 2H), 7.58-7.78 (m, 5H), 8.09(d, J=7.4, 2H), 12.38 (s, 1H)

6-Butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-one    sodium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-one    potassium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-one    hydrochloride-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(5-phenyl-1,2,4-oxadiazol-3-yl)methyl]pyrimidin-4(3H)-one    hydrobromide

Example 1536-butyl-3-(2-fluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

153a)4′-{[4-butyl-1-(2-fluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.23 g), potassium carbonate (0.96 g), 1-(bromomethyl)-2-fluorobenzene(0.66 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.93 g, 59%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.4, 3H), 1.30-1.45 (m, 2H),1.53-1.66 (m, 2H), 2.42 (s, 3H), 2.58-2.65 (m, 2H), 4.03 (s, 2H), 5.34(s, 2H), 6.99-7.10 (m, 3H), 7.16-7.26 (m, 1H), 7.33 (td, J=7.5, 0.9,1H), 7.38-7.50 (m, 5H), 7.54 (td, J=7.7, 1.1, 1H), 7.67 (d, J=7.7, 1H)

153b)6-butyl-3-(2-fluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.23 g), sodium hydrogencarbonate (1.75 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2-fluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.93 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (0.50 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.82 g,78%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (t, J=7.4, 3H), 1.34-1.47 (m, 2H),1.54-1.69 (m, 2H), 2.40 (s, 3H), 2.55-2.65 (m, 2H), 3.93 (s, 2H), 5.24(s, 2H), 6.90-6.99 (m, 1H), 7.02-7.14 (m, 2H), 7.18-7.32 (m, 5H),7.38-7.48 (m, 2H), 7.57 (td, J=7.6, 1.1, 1H), 7.77 (d, J=7.6, 1H), 12.39(s, 1H)

Example 1543-[(4-benzylmorpholin-2-yl)methyl]-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

154a)4′-({1-[(4-benzylmorpholin-2-yl)methyl]-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.25 g), potassium carbonate (0.96 g),4-benzyl-2-(chloromethyl)morpholine (0.87 g) and N,N-dimethylformamide(20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless viscoussubstance (0.62 g, 34%).

¹H NMR (300 MHz, CDCl₃) δ 0.76 (t, J=7.2, 3H), 1.15-1.28 (m, 2H),1.36-1.49 (m, 2H), 1.74-1.82 (m, 1H), 1.90-2.01 (m, 1H), 2.39-2.47 (m,6H), 2.76 (d, J=10.6, 1H), 3.26-3.43 (m, 3H), 3.55-3.66 (m, 2H),3.73-3.89 (m, 3H), 4.04-4.11 (m, 1H), 7.02-7.16 (m, 5H), 7.17-7.33 (m,6H), 7.39 (td, J=7.7, 1.3, 1H), 7.52 (dd, J=7.6, 1.1, 1H)

154b)3-[(4-benzylmorpholin-2-yl)methyl]-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.23 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C.for 30 min,4′-({1-[(4-benzylmorpholin-2-yl)methyl]-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.62 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.30 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.11 g,15%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (t, J=7.2, 3H), 1.19-1.34 (m, 2H),1.35-1.50 (m, 2H), 1.88-2.00 (m, 1H), 2.06-2.19 (m, 1H), 2.41-2.49 (m,2H), 2.63 (d, J=11, 1H), 2.79 (d, J=11, 1H), 3.32 (s, 2H), 3.43 (t,J=11, 2H), 3.53 (s, 2H), 3.69-3.95 (m, 5H), 4.03-4.12 (m, 1H), 7.16-7.38(m, 9H), 7.45-7.58 (m, 2H), 7.62-7.72 (m, 2H), 12.30 (s, 1H)

Example 1556-butyl-2-methyl-3-[4-(morpholin-4-ylcarbonyl)benzyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

155a)4′-({4-butyl-2-methyl-1-[4-(morpholin-4-ylcarbonyl)benzyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),4-[4-(chloromethyl)benzoyl]morpholine (0.87 g) and N,N-dimethylformamide(20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.16 g,61%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.2, 3H), 1.30-1.45 (m, 2H),1.52-1.67 (m, 2H), 2.43 (s, 3H), 2.57-2.65 (m, 2H), 2.83 (s, 1H), 2.89(s, 1H), 3.29-3.86 (m, 6H), 4.02 (s, 2H), 5.32 (s, 2H), 7.23 (d, J=8.0,2H), 7.38 (t, J=6.8, 5H), 7.45-7.51 (m, 3H), 7.60 (t, J=7.6, 1H), 7.71(d, J=8.0, 1H)

155b)6-butyl-2-methyl-3-[4-(morpholin-4-ylcarbonyl)benzyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.33 g), sodium hydrogencarbonate (1.83 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-1-[4-(morpholin-4-ylcarbonyl)benzyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.16 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.46 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (1.01 g,78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.2, 3H), 1.22-1.36 (m, 2H),1.39-1.53 (m, 2H), 2.40 (s, 3H), 2.47-2.55 (m, 2H), 3.32 (s, 3H),3.49-3.68 (m, 5H), 3.90 (s, 2H), 5.32 (s, 2H), 7.18-7.28 (m, 6H), 7.41(d, J=8.0, 2H), 7.53 (dd, J=16.1, 7.8, 2H), 7.62-7.72 (m, 2H), 12.39 (s,1H)

Example 1563-(1H-1,2,3-benzotriazol-1-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

156a)4′-{[1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),1-(chloromethyl)-1H-1,2,3-benzotriazole (0.62 g) andN,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.55 g, 33%).

¹H NMR (300 MHz, CDCl₃) δ 0.87 (t, J=7.4, 3H), 1.28-1.41 (m, 2H),1.47-1.60 (m, 2H), 2.52-2.60 (m, 2H), 2.96 (s, 3H), 3.98 (s, 2H), 6.86(s, 2H), 7.30-7.40 (m, 4H), 7.42-7.54 (m, 4H), 7.61 (t, J=7.6, 1H), 7.73(d, J=7.6, 1H), 8.02 (d, J=8.3, 1H), 8.10 (d, J=8.3, 1H)

156b)3-(1H-1,2,3-benzotriazol-1-ylmethyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.73 g), sodium hydrogencarbonate (1.02 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,4′-{[1-(1H-1,2,3-benzotriazol-1-ylmethyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.55 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.23 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.35 g,56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (t, J=7.2, 3H), 1.18-1.34 (m, 2H),1.34-1.49 (m, 2H), 2.48-2.51 (m, 2H), 2.86 (s, 3H), 3.84 (s, 2H), 6.90(s, 2H), 7.16-7.24 (m, 4H), 7.40-7.52 (m, 2H), 7.53-7.72 (m, 4H),8.05-8.13 (m, 2H), 12.38 (s, 1H)

Example 1576-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-{[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]methyl}pyrimidin-4(3H)-one

157a)4′-[(4-butyl-2-methyl-6-oxo-1-{[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]methyl}-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.23 g), potassium carbonate (0.94 g),3-(chloromethyl)-5-(3-thienyl)-1,2,4-oxadiazole (0.75 g) andN,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.79 g, 44%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.3, 3H), 1.30-1.45 (m, 2H),1.51-1.64 (m, 2H), 2.56-2.62 (m, 5H), 4.00 (s, 2H), 5.43 (s, 2H),7.32-7.48 (m, 7H), 7.53-7.61 (m, 2H), 7.69 (d, J=7.7, 1H), 8.15-8.18 (m,1H)

157b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-{[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.27 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(4-butyl-2-methyl-6-oxo-1-{[5-(3-thienyl)-1,2,4-oxadiazol-3-yl]methyl}-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.79 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.32 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.22 g,25%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.3, 3H), 1.22-1.36 (m, 2H),1.39-1.53 (m, 2H), 2.55 (s, 3H), 3.32 (s, 2H), 3.86 (s, 2H), 5.44 (s,2H), 7.17-7.25 (m, 4H), 7.45-7.52 (m, 1H), 7.52-7.58 (m, 1H), 7.61-7.71(m, 3H), 7.84 (dd, J=5.1, 3.0, 1H), 8.60 (dd, J=2.9, 1.2, 1H), 12.37 (s,1H)

Example 1586-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(quinolin-2-ylmethyl)pyrimidin-4(3H)-one

158a)4′-{[4-butyl-2-methyl-6-oxo-1-(quinolin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),2-(chloromethyl)quinolinehydrochloride (0.73 g) andN,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow solid (0.49 g, 26%).

¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, J=7.3, 3H), 1.32-1.46 (m, 2H),1.53-1.66 (m, 2H), 2.58-2.65 (m, 5H), 4.01 (s, 2H), 5.57 (s, 2H),7.35-7.41 (m, 4H), 7.42-7.56 (m, 4H), 7.61 (td, J=7.7, 1.2, 1H),7.67-7.76 (m, 2H), 7.79 (d, J=8.1, 1H), 8.01 (d, J=8.5, 1H), 8.14 (d,J=8.5, 1H)

158b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(quinolin-2-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.51 g), sodium hydrogencarbonate (0.75 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(quinolin-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.49 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (8 mL), N,N′-carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.20 g,38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.4, 3H), 1.23-1.37 (m, 2H),1.42-1.57 (m, 2H), 2.42-2.57 (m, 2H), 3.33 (s, 3H), 3.88 (s, 2H), 5.54(s, 2H), 7.17-7.28 (m, 4H), 7.46-7.53 (m, 2H), 7.53-7.78 (m, 5H), 7.85(d, J=7.4, 1H), 7.97 (d, J=7.4, 1H), 8.38 (d, J=8.5, 1H), 12.37 (s, 1H)

Example 1596-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1,3-thiazol-4-ylmethyl)pyrimidin-4(3H)-one

159a)4′-{[4-butyl-2-methyl-6-oxo-1-(1,3-thiazol-4-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-1,3-thiazolehydrochloride (0.58 g) and N,N-dimethylformamide (20 mL) was stirred at90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.01 g,66%).

¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, J=7.2, 3H), 1.28-1.42 (m, 2H),1.49-1.62 (m, 2H), 2.54-2.62 (m, 2H), 2.71 (s, 3H), 3.98 (s, 2H), 5.38(s, 2H), 7.31-7.49 (m, 7H), 7.56 (td, J=7.6, 1.1, 1H), 7.68 (d, J=8.0,1H), 8.69-8.75 (m, 1H)

159b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(1,3-thiazol-4-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.32 g), sodium hydrogencarbonate (1.87 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(1,3-thiazol-4-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.01 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.36 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.34 g,30%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.78 (t, J=7.3, 3H), 1.20-1.32 (m, 2H),1.36-1.49 (m, 2H), 2.42-2.48 (m, 2H), 2.57 (s, 3H), 3.82 (s, 2H), 5.32(s, 2H), 7.19 (d, J=8.3, 2H), 7.38-7.52 (m, 4H), 7.54-7.60 (m, 1H),7.79-7.82 (m, 1H), 8.46-8.48 (m, 1H), 9.04 (d, J=1.9, 1H), 12.35 (s, 1H)

Example 1606-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one

160a)4′-{[4-butyl-2-methyl-6-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),2-(bromomethyl)tetrahydro-2H-pyran (0.61 g) and N,N-dimethylformamide(20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless viscoussubstance (0.71 g, 46%).

¹H NMR (300 MHz, CDCl₃) δ 0.78 (t, J=7.3, 3H), 1.18-1.31 (m, 3H),1.30-1.52 (m, 5H), 1.62 (m, 1H), 1.71 (s, 1H), 2.43-2.52 (m, 5H),3.11-3.23 (m, 1H), 3.52-3.65 (m, 2H), 3.73-3.93 (m, 3H), 4.08-4.19 (m,1H), 7.21-7.29 (m, 3H), 7.30-7.38 (m, 3H), 7.45 (td, J=7.7, 1.2, 1H),7.58 (dd, J=7.7, 0.9, 1H)

160b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogencarbonate (1.31 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.71 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.34 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.26 g,33%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.3, 3H), 1.21-1.35 (m, 3H),1.36-1.51 (m, 5H), 1.63 (d, J=12.1, 1H), 1.78 (br s., 1H), 2.45 (d,J=7.9, 1H), 2.53 (s, 3H), 3.17-3.29 (m, 1H), 3.51-3.66 (m, 2H),3.76-3.94 (m, 4H), 4.09 (dd, J=14.0, 2.4, 1H), 7.17-7.27 (m, 4H),7.47-7.53 (m, 1H), 7.55 (dd, J=7.4, 1.1, 1H), 7.62-7.72 (m, 2H), 12.38(s, 1H)

6-Butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    sodium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    potassium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    hydrochloride-   6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydro-2H-pyran-2-ylmethyl)pyrimidin-4(3H)-one    hydrobromide

Example 1616-butyl-3-(2,5-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

161a)4′-{[4-butyl-1-(2,5-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),2-(bromomethyl)-1,4-difluorobenzene (1.06 g) and N,N-dimethylformamide(20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.88 g, 54%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.4, 3H), 1.30-1.45 (m, 2H),1.54-1.66 (m, 2H), 2.44 (s, 3H), 2.58-2.67 (m, 2H), 4.03 (s, 2H), 5.31(s, 2H), 6.76-6.84 (m, 1H), 6.86-6.96 (m, 1H), 6.97-7.06 (m, 1H),7.31-7.51 (m, 6H), 7.53-7.59 (m, 1H), 7.69 (dd, J=7.8, 1.0, 1H)

161b)6-butyl-3-(2,5-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.08 g), sodium hydrogencarbonate (1.53 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,5-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.88 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.38 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.67 g,68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.4, 3H), 1.24-1.35 (m, 2H),1.41-1.52 (m, 2H), 2.43 (s, 3H), 2.48-2.53 (m, 1H), 3.88 (s, 2H), 5.27(s, 2H), 6.77-6.84 (m, 1H), 7.16-7.26 (m, 5H), 7.28-7.37 (m, 1H),7.47-7.53 (m, 1H), 7.56 (dd, J=7.6, 1.1, 2H), 7.63-7.72 (m, 2H), 12.38(s, 1H)

Example 1626-butyl-3-(3,3-dimethyl-2-oxobutyl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methylpyrimidin-4(3H)-one

162a)4′-{[4-butyl-1-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(1.22 g), cesium carbonate (1.73 g), 1-bromo-3,3-dimethylbutan-2-one(0.71 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.86 g, 34%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.3, 3H), 1.27-1.42 (m, 2H), 1.29(s, 9H), 1.50-1.62 (m, 2H), 2.34 (s, 3H), 2.52-2.60 (m, 2H), 3.96 (s,2H), 5.08 (s, 2H), 7.19-7.28 (m, 3H), 7.39-7.47 (m, 2H), 7.57-7.65 (m,1H), 7.72 (d, J=7.3, 1H)

162b)6-butyl-3-(3,3-dimethyl-2-oxobutyl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methylpyrimidin-4(3H)-one

4′-{[4-Butyl-1-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(3.82 g) and methanol (100 mL) were ice-cooled, sodium borohydride (0.92g) was gradually added, and the mixture was stirred for 30 min.Thereafter, the temperature of the mixture was gradually raised to roomtemperature, and the mixture was stirred for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. A mixture of hydroxylammoniumchloride (1.08 g), sodium hydrogen carbonate (1.53 g) and dimethylsulfoxide (50 mL) was stirred at 40° C. for 30 min, the residue (4.44 g)was added, and the mixture was stirred at 90° C. for 16 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (100 mL), N,N′-carbonyldiimidazole (2.26 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (2.05 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in methylene chloride (80 mL),1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.78 g) wasadded, and the mixture was stirred at room temperature for 2 hr. Asaturated aqueous sodium hydrogen carbonate and sodium thiosulfatepentahydrate were added to the reaction mixture, and the mixture wasstirred at room temperature for 2 hr. The reaction mixture was dilutedwith chloroform, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (1.80 g,18%).

¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, J=7.3, 3H), 1.27 (s, 9H), 1.32-1.46(m, 2H), 1.54-1.67 (m, 2H), 2.33 (s, 3H), 2.56-2.64 (m, 2H), 3.88 (s,2H), 5.01 (s, 2H), 6.93-7.15 (m, 3H), 7.40 (dd, J=7.7, 1.1, 1H), 7.49(td, J=7.6, 1.3, 1H), 7.60 (td, J=7.6, 1.4, 1H), 7.80 (dd, J=7.7, 1.3,1H), 12.39 (s, 1H)

Example 1636-butyl-2-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

163a)4′-({4-butyl-2-methyl-1-[(2-methyl-1,3-thiazol-4-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (0.63 g) andN,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow solid (0.94 g, 55%).

¹H NMR (300 MHz, CDCl₃) δ 0.80 (t, J=7.2, 3H), 1.20-1.33 (m, 2H),1.40-1.54 (m, 2H), 2.46-2.52 (m, 2H), 2.54 (s, 3H), 2.61 (s, 3H), 3.89(s, 2H), 5.20 (s, 2H), 7.00 (s, 1H), 7.23-7.32 (m, 3H), 7.32-7.41 (m,3H), 7.47 (t, J=7.7, 1H), 7.60 (d, J=7.7, 1H)

163b)6-butyl-2-methyl-3-[(2-methyl-1,3-thiazol-4-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.19 g), sodium hydrogencarbonate (1.69 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-1-[(2-methyl-1,3-thiazol-4-yl)methyl]-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.94 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (25 mL), N,N′-carbonyldiimidazole (0.47 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.43 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.93 g,87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.2, 3H), 1.20-1.35 (m, 2H),1.36-1.52 (m, 2H), 2.43-2.49 (m, 2H), 2.58 (s, 3H), 2.62 (s, 3H), 3.85(s, 2H), 5.23 (s, 2H), 7.16-7.26 (m, 4H), 7.28 (s, 1H), 7.49 (d, J=8.0,1H), 7.55 (d, J=7.6, 1H), 7.62-7.72 (m, 2H), 12.38 (s, 1H)

Example 1646-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydrofuran-2-ylmethyl)pyrimidin-4(3H)-one

164a)4′-{[4-butyl-2-methyl-6-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g), 2-(bromomethyl)tetrahydrofuran(0.56 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless viscous substance (0.94 g, 55%).

¹H NMR (300 MHz, CDCl₃) δ 0.74 (t, J=7.4, 3H), 1.14-1.28 (m, 2H),1.35-1.51 (m, 3H), 1.61-1.80 (m, 2H), 1.87-1.99 (m, 1H), 2.39-2.46 (m,2H), 2.45 (s, 3H), 3.50-3.76 (m, 3H), 3.80-3.97 (m, 2H), 4.04-4.16 (m,1H), 4.19-4.26 (m, 1H), 7.16-7.25 (m, 3H), 7.26-7.33 (m, 3H), 7.40 (t,J=7.6, 1H), 7.53 (d, J=8.0, 1H)

164b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(tetrahydrofuran-2-ylmethyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.82 g), sodium hydrogencarbonate (1.16 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(tetrahydrofuran-2-ylmethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.61 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.32 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.61 g,89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.2, 3H), 1.20-1.35 (m, 2H),1.37-1.50 (m, 2H), 1.52-1.66 (m, 1H), 1.74-1.92 (m, 2H), 1.92-2.06 (m,1H), 2.43-2.54 (m, 5H), 3.58-3.67 (m, 1H), 3.73-3.91 (m, 4H), 4.04-4.25(m, 2H), 7.16-7.28 (m, 4H), 7.47-7.58 (m, 2H), 7.60-7.73 (m, 2H), 12.37(s, 1H)

Example 1656-butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

165a)4′-{[4-butyl-1-(2,6-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),2-(bromomethyl)-1,3-difluorobenzene (0.56 g) and N,N-dimethylformamide(20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow solid (0.40g, 55%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.3, 3H), 1.28-1.41 (m, 2H),1.49-1.62 (m, 2H), 2.51 (s, 3H), 2.52-2.59 (m, 2H), 3.98 (s, 2H), 5.38(s, 2H), 6.82-6.93 (m, 2H), 7.17-7.28 (m, 1H), 7.31-7.40 (m, 3H), 7.45(d, J=8.3, 3H), 7.58 (td, J=7.7, 1.3, 1H), 7.70 (dd, J=7.7, 1.1, 1H)

165b)6-butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.49 g), sodium hydrogencarbonate (0.70 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,6-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.40 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.34 g,75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (t, J=7.2, 3H), 1.20-1.32 (m, 2H),1.37-1.48 (m, 2H), 2.42-2.51 (m, 2H), 2.50 (s, 3H), 3.81 (s, 2H), 5.30(s, 2H), 7.05-7.12 (m, 2H), 7.17-7.21 (m, 4H), 7.35-7.43 (m, 1H),7.47-7.57 (m, 2H), 7.61-7.72 (m, 2H), 12.38 (s, 1H)

6-Butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(2,6-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 1666-butyl-3-(2,4-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

166a)4′-{[4-butyl-1-(2,4-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),1-(bromomethyl)-2,4-difluorobenzene (0.70 g) and N,N-dimethylformamide(20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow solid (0.82g, 50%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.4, 3H), 1.31-1.45 (m, 2H),1.53-1.64 (m, 2H), 2.46 (s, 3H), 2.58-2.65 (m, 2H), 4.01 (s, 2H), 5.29(s, 2H), 6.79-6.89 (m, 2H), 7.07-7.16 (m, 1H), 7.35-7.42 (m, 3H),7.45-7.50 (m, 3H), 7.59 (td, J=7.6, 1.1, 1H), 7.70-7.74 (m, 1H)

166b)6-butyl-3-(2,4-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.00 g), sodium hydrogencarbonate (1.43 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,4-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.82 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (25 mL), N,N′-carbonyldiimidazole (0.41 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.85 g,93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.4, 3H), 1.21-1.36 (m, 2H),1.38-1.51 (m, 2H), 2.42 (s, 3H), 3.27-3.42 (m, 2H), 3.88 (s, 2H), 5.25(s, 2H), 6.98-7.12 (m, 2H), 7.19-7.26 (m, 3H), 7.31 (td, J=10.0, 2.3,2H), 7.50 (d, J=8.0, 1H), 7.56 (d, J=7.6, 1H), 7.62-7.72 (m, 2H), 12.39(s, 1H)

Example 1676-butyl-3-(2,3-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

167a)4′-{[4-butyl-1-(2,3-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),1-(bromomethyl)-2,3-difluorobenzene (0.70 g) and N,N-dimethylformamide(20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.76 g,46%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.4, 3H), 1.31-1.45 (m, 2H),1.54-1.67 (m, 2H), 2.45 (s, 3H), 2.58-2.65 (m, 2H), 4.02 (s, 2H), 5.36(s, 2H), 6.78-6.85 (m, 1H), 6.98-7.12 (m, 2H), 7.32-7.42 (m, 3H),7.42-7.51 (m, 3H), 7.57 (td, J=7.7, 1.3, 1H), 7.67-7.71 (m, 1H)

167b)6-butyl-3-(2,3-difluorobenzyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.93 g), sodium hydrogencarbonate (1.33 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,3-difluorobenzyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.32 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.72 g,84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.1, 3H), 1.23-1.37 (m, 2H),1.38-1.53 (m, 2H), 2.43 (s, 3H), 2.48-2.51 (m, 2H), 3.88 (s, 2H), 5.33(s, 2H), 6.73-6.80 (m, 1H), 7.14-7.27 (m, 5H), 7.32-7.44 (m, 1H),7.47-7.53 (m, 1H), 7.56 (dd, J=7.5, 1.1, 1H), 7.63-7.72 (m, 2H), 12.39(s, 1H)

Example 1686-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(2-phenyl-1,3-thiazol-4-yl)methyl]pyrimidin-4(3H)-one

168a)4′-({4-butyl-2-methyl-6-oxo-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),4-(chloromethyl)-2-phenyl-1,3-thiazole (0.71 g) andN,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (1.20 g, 66%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.2, 3H), 1.28-1.41 (m, 2H),1.51-1.63 (m, 2H), 2.55-2.61 (m, 2H), 2.80 (s, 3H), 3.99 (s, 2H), 5.34(s, 2H), 7.26-7.42 (m, 8H), 7.43-7.53 (m, 3H), 7.63-7.67 (m, 1H),7.85-7.89 (m, 2H)

168b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(2-phenyl-1,3-thiazol-4-yl)methyl]pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.34 g), sodium hydrogencarbonate (1.90 g) and dimethyl sulfoxide (18 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-6-oxo-1-[(2-phenyl-1,3-thiazol-4-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.20 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.42 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.38 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.80 g,60%).

¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, J=7.2, 3H), 1.33-1.46 (m, 2H),1.50-1.68 (m, 2H), 2.56-2.66 (m, 2H), 2.81 (s, 3H), 3.90 (s, 2H), 5.29(s, 2H), 7.19-7.32 (m, 5H), 7.37-7.50 (m, 5H), 7.59 (td, J=7.6, 1.5,1H), 7.82 (dd, J=8.0, 1.1, 1H), 7.87-7.94 (m, 2H), 12.38 (s, 1H)

Example 1696-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(2-pyridin-2-yl-1,3-thiazol-4-yl)methyl]pyrimidin-4(3H)-one

169a)4′-({4-butyl-2-methyl-6-oxo-1-[(2-pyridin-2-yl-1,3-thiazol-4-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),2-[4-(chloromethyl)-1,3-thiazol-2-yl]pyridine (0.72 g) andN,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow solid (0.80 g, 44%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.2, 3H), 1.28-1.43 (m, 2H),1.52-1.63 (m, 2H), 2.56-2.63 (m, 2H), 2.81 (s, 3H), 4.01 (s, 2H), 5.39(s, 2H), 7.19-7.25 (m, 1H), 7.32 (t, J=7.6, 1H), 7.38-7.56 (m, 7H),7.64-7.74 (m, 2H), 8.08 (d, J=8.0, 1H), 8.52 (d, J=4.2, 1H)

169b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(2-pyridin-2-yl-1,3-thiazol-4-yl)methyl]pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.26 g) and dimethyl sulfoxide (18 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-2-methyl-6-oxo-1-[(2-pyridin-2-yl-1,3-thiazol-4-yl)methyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.80 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.30 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.44 g,49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.2, 3H), 1.21-1.35 (m, 2H),1.38-1.52 (m, 2H), 2.44-2.53 (m, 2H), 2.67 (s, 3H), 3.87 (s, 2H), 5.36(s, 2H), 7.17-7.28 (m, 4H), 7.44-7.59 (m, 3H), 7.62-7.71 (m, 3H), 7.95(td, J=7.8, 1.9, 1H), 8.01-8.06 (m, 1H), 8.62 (d, J=4.2, 1H), 12.38 (s,1H)

Example 1706-butyl-3-(2,3-dihydro-1-benzofuran-2-ylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

170a)4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-2-ylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), 2,3-dihydro-1-benzofuran-2-ylmethanol (1.02 g),tributylphosphine (2.1 mL),1,1′-[(E)-diazene-1,2-diyldicarbonyl]dipiperidine (1.72 g) andtetrahydrofuran (60 mL) was stirred at room temperature for 4 hr. Thereaction mixture was diluted with ethyl acetate, and the insoluble solidwas filtered off. The solvent of the filtrate was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a colorless viscoussubstance (0.86 g, 52%).

¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.3, 3H), 1.28-1.43 (m, 2H),1.52-1.65 (m, 2H), 2.57 (s, 3H), 2.68-2.76 (m, 2H), 2.93 (dd, J=16, 6.7,1H), 3.20 (dd, J=15.7, 9.7, 1H), 3.79-3.94 (m, 2H), 4.54 (s, 2H),4.98-5.09 (m, 1H), 6.71-6.82 (m, 2H), 7.00-7.11 (m, 2H), 7.17 (d, J=7.9,2H), 7.32 (t, J=7.7, 1H), 7.38-7.45 (m, 3H), 7.54 (t, J=7.6, 1H), 7.66(d, J=7.6, 1H)

170b)6-butyl-3-(2,3-dihydro-1-benzofuran-2-ylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.04 g), sodium hydrogencarbonate (1.49 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-2-ylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.86 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.05 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.07 g,7%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2, 3H), 1.23-1.36 (m, 2H),1.37-1.51 (m, 2H), 2.44-2.55 (m, 4H), 2.99-3.08 (m, 1H), 3.34-3.46 (m,1H), 3.54-3.65 (m, 1H), 3.82-3.95 (m, 2H), 4.10 (dd, J=14.4, 9.5, 1H),4.27-4.35 (m, 1H), 5.05-5.15 (m, 1H), 6.79 (d, J=8.0, 1H), 6.87 (t,J=7.0, 1H), 7.09-7.16 (m, 1H), 7.20-7.28 (m, 5H), 7.48-7.58 (m, 2H),7.63-7.72 (m, 2H), 12.40 (s, 1H)

Example 1716-butyl-3-[3-(1-hydroxyethyl)benzyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

171a)4′-{[1-(3-acetylbenzyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.22 g), potassium carbonate (0.94 g),1-[3-(bromomethyl)phenyl]ethanone (0.73 g) and N,N-dimethylformamide (20mL) was stirred at 90° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless viscoussubstance (1.02 g, 61%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.2, 3H), 1.30-1.44 (m, 2H),1.52-1.65 (m, 2H), 2.44 (s, 3H), 2.51 (s, 3H), 2.57-2.65 (m, 2H), 4.04(s, 2H), 5.35 (s, 2H), 7.33-7.53 (m, 8H), 7.58 (t, J=7.6, 1H), 7.69 (d,J=7.6, 1H), 7.80-7.88 (m, 2H)

171b)6-butyl-3-[3-(1-hydroxyethyl)benzyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

4′-{[1-(3-acetylbenzyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.02 g) and methanol (30 mL) were ice-cooled, sodium borohydride (0.24g) was gradually added, and the mixture was stirred for 30 min.Thereafter, the temperature of the mixture was gradually raised to roomtemperature, and the mixture was stirred for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. A mixture of hydroxylammoniumchloride (1.17 g), sodium hydrogen carbonate (1.66 g) and dimethylsulfoxide (18 mL) was stirred at 40° C. for 30 min, the residue obtainedabove (0.97 g) was added, and the mixture was stirred at 90° C. for 16hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas dissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.35g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.60 g,53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.3, 3H), 1.19-1.34 (m, 3H),1.39-1.51 (m, 2H), 1.62 (d, J=6.6, 1H), 2.39 (s, 3H), 2.44-2.55 (m, 4H),3.38 (q, J=7.0, 1H), 3.88-3.93 (m, 2H), 5.27-5.33 (m, 2H), 7.12 (d,J=7.2, 1H), 7.17-7.30 (m, 5H), 7.34-7.45 (m, 2H), 7.46-7.59 (m, 2H),7.63-7.73 (m, 2H), 12.41 (s, 1H)

Example 1726-ethyl-2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

172a)4′-[(4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of methyl 3-oxopentanoate (5.73 g) and tetrahydrofuran (120mL) was ice-cooled to 0° C., 60% sodium hydride (1.32 g) was graduallyadded, and the mixture was stirred in situ for 30 min. To the mixturewas added 4′-(bromomethyl)biphenyl-2-carbonitrile (5.99 g), and themixture was stirred for 30 min. Thereafter, the temperature of themixture was gradually raised to room temperature, and the mixture wasstirred for 4 hr. The solvent of the reaction mixture was evaporatedunder reduced pressure, and the residue was diluted with ethyl acetate.The diluted solution was washed with water and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. To an ice-cooled mixture of acetamidine hydrochloride(4.16 g) and methanol (36 mL) was added dropwise 28% sodiummethoxide-methanol solution (17.8 mL), and a mixture of theaforementioned residue, 1,4-dioxane (24 mL) and methanol (36 mL) wasadded dropwise. The mixture was stirred at room temperature for 12 hr.The solvent was evaporated under reduced pressure. The residue wasdiluted with ethyl acetate, and the diluted solution was washed with 0.1M aqueous hydrochloric acid solution, water and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give crude crystals. The crude crystals were washedwith diisopropyl ether to give the title compound as a colorless solid(4.66 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.04 (t, J=7.4, 3H), 2.26 (s, 3H), 2.46-2.55(m, 2H), 3.86 (s, 2H), 7.33 (d, J=8.3, 2H), 7.48 (d, J=8.3, 2H),7.52-7.64 (m, 2H), 7.73-7.81 (m, 1H), 7.93 (d, J=7.5, 1H), 12.35 (s, 1H)

172b)4′-{[4-ethyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.99 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.98 g),molecular sieves 4 A (0.49 g), triethylamine (2.1 mL), pyridine (1.0mL), copper(II) acetate (1.09 g) and methylene chloride (20 mL) wasstirred at room temperature for 24 hr. Ethyl acetate was added to thereaction mixture, and the insoluble solid was filtered off. The solventof the filtrate was evaporated under reduced pressure, and the residuewas purified by silica gel column chromatography to give the titlecompound as colorless crystals (1.08 g, 78%).

¹H NMR (300 MHz, CDCl₃) δ 1.23 (t, J=7.5, 3H), 1.50 (dd, J=10.7, 6.2,3H), 2.20 (d, J=4.7, 3H), 2.70 (q, J=7.4, 2H), 2.81-2.96 (m, 1H),3.30-3.42 (m, 1H), 3.97 (s, 2H), 4.93-5.09 (m, 1H), 6.82-6.86 (m, 1H),6.90-6.97 (m, 1H), 6.99 (d, J=1.1, 1H), 7.37-7.51 (m, 6H), 7.58-7.66 (m,1H), 7.74 (dd, J=7.7, 0.8, 1H)

172c)6-ethyl-2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.38 g), sodium hydrogencarbonate (1.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.08 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (40 mL), N,N′-carbonyldiimidazole (0.65 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.60 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.82 g,67%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.07 (t, J=6.6, 3H), 1.42 (dd, J=6.1, 2.7,3H), 2.09 (d, J=3.0, 3H), 2.48-2.52 (m, 2H), 2.77-2.89 (m, 1H),3.19-3.53 (m, 1H), 3.86 (s, 2H), 4.91-5.05 (m, 1H), 6.83 (d, J=8.3, 1H),7.05 (dd, J=8.3, 1.7, 1H), 7.16 (d, J=1.9, 1H), 7.19-7.31 (m, 4H),7.49-7.58 (m, 2H), 7.63-7.72 (m, 2H), 12.37 (s, 1H)

Example 1736-ethyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

173a)4′-[(4-ethyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.99 g), phenylboronic acid (0.73 g), molecular sieves 4 A (0.49 g),triethylamine (2.1 mL), pyridine (1.0 mL), copper(II) acetate (1.09 g)and methylene chloride (20 mL) was stirred at room temperature for 24hr. Ethyl acetate was added to the reaction mixture, and the insolublesolid was filtered off. The solvent of the filtrate was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.42 g,34%).

¹H NMR (300 MHz, CDCl₃) δ 1.24 (t, J=7.6, 3H), 2.17 (s, 3H), 2.71 (q,J=7.6, 2H), 3.98 (s, 2H), 7.21-7.28 (m, 3H), 7.38-7.42 (m, 1H),7.42-7.46 (m, 3H), 7.46-7.57 (m, 4H), 7.62 (td, J=7.7, 1.4, 1H), 7.74(dd, J=7.7, 0.9, 1H)

173b)6-ethyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.61 g), sodium hydrogencarbonate (0.87 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(4-ethyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.42 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.30 g,62%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.08 (t, J=7.5, 3H), 2.49-2.53 (m, 2H), 3.35(s, 3H), 3.87 (s, 2H), 7.18-7.32 (m, 4H), 7.36-7.43 (m, 2H), 7.48-7.59(m, 5H), 7.62-7.72 (m, 2H), 12.40 (s, 1H)

Example 1746-cyclopropyl-2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

174a)4′-[(4-cyclopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of methyl 3-cyclopropyl-3-oxopropanoate (5.99 g) andtetrahydrofuran (120 mL) was ice-cooled at 0° C., 60% sodium hydride(1.32 g) was gradually added, and the mixture was stirred in situ for 30min. To a mixture was added 4′-(bromomethyl)biphenyl-2-carbonitrile(5.99 g), and the mixture was stirred for 30 min. Then, the temperatureof the mixture was gradually raised to room temperature, and the mixturewas stirred for 4 hr. The solvent was evaporated under reduced pressure,and the residue was diluted with ethyl acetate. The diluted solution waswashed with water and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure. Toan ice-cooled mixture of acetamidine hydrochloride (4.16 g) and methanol(36 mL) was added dropwise 28% sodium methoxide-methanol solution (17.8mL), and a mixture of the aforementioned residue, 1,4-dioxane (24 mL)and methanol (36 mL) was added dropwise. The mixture was stirred at roomtemperature for 12 hr. The solvent of the reaction mixture wasevaporated under reduced pressure, and the residue was diluted withethyl acetate, and the diluted solution was washed with 0.1 M aqueoushydrochloric acid solution, water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give crude crystals. The crude crystals were washed withdiisopropyl ether to give the title compound as a colorless solid (3.10g, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.92 (m, 2H), 0.93-1.00 (m, 2H),2.10-2.18 (m, 1H), 2.19 (s, 3H), 3.98 (s, 2H), 7.37-7.43 (m, 2H),7.46-7.65 (m, 4H), 7.74-7.82 (m, 1H), 7.93 (d, J=7.72, 1H), 12.24 (s,1H)

174b)4′-{[4-cyclopropyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-cyclopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.02 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.73 g),molecular sieves 4 A (0.51 g), triethylamine (2.1 mL), pyridine (1.0mL), copper(II) acetate (1.09 g) and methylene chloride (20 mL) wasstirred at room temperature for 24 hr. Ethyl acetate was added to thereaction mixture, and the insoluble solid was filtered off. The solventof the filtrate was evaporated under reduced pressure, and the residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (0.81 g, 57%).

¹H NMR (300 MHz, CDCl₃) δ 0.93-1.01 (m, 2H), 1.16-1.22 (m, 2H), 1.48(dd, J=10.7, 6.2, 3H), 2.09-2.20 (m, 4H), 2.79-2.91 (m, 1H), 3.27-3.40(m, 1H), 4.09 (s, 2H), 4.91-5.06 (m, 1H), 6.79-6.83 (m, 1H), 6.86-6.91(m, 1H), 6.95 (s, 1H), 7.39 (td, J=7.6, 1.1, 1H), 7.43-7.51 (m, 5H),7.61 (td, J=7.7, 1.3, 1H), 7.73 (dd, J=7.8, 1.0, 1H)

174c)6-cyclopropyl-2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.02 g), sodium hydrogencarbonate (1.19 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-cyclopropyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.81 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.18 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.32 g,35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-0.94 (m, 2H), 1.41 (dd, J=6.3, 1.7,3H), 2.02 (d, J=3.0, 3H), 2.10-2.21 (m, 1H), 2.48-2.53 (m, 2H),2.75-2.88 (m, 1H), 3.27-3.42 (m, 1H), 3.98 (s, 2H), 4.91-5.06 (m, 1H),6.82 (d, J=8.3, 1H), 6.98-7.04 (m, 1H), 7.13 (d, J=1.9, 1H), 7.20-7.26(m, 2H), 7.30-7.36 (m, 2H), 7.49-7.58 (m, 2H), 7.63-7.73 (m, 2H), 12.41(s, 1H)

Example 1756-cyclopropyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

175a)4′-[(4-cyclopropyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-cyclopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.02 g), phenylboronic acid (0.73 g), molecular sieves 4 A (0.51 g),triethylamine (2.1 mL), pyridine (1.0 mL), copper(II) acetate (1.09 g)and methylene chloride (20 mL) was stirred at room temperature for 24hr. Ethyl acetate was added to the reaction mixture, and the insolublesolid was filtered off. The solvent of the filtrate was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.44 g,35%).

¹H NMR (300 MHz, CDCl₃) δ 0.94-1.02 (m, 2H), 1.17-1.22 (m, 2H), 2.08 (s,3H), 2.11-2.21 (m, 1H), 4.10 (s, 2H), 7.18-7.23 (m, 2H), 7.40 (td,J=7.6, 1.2, 1H), 7.43-7.55 (m, 8H), 7.61 (td, J=7.7, 1.4, 1H), 7.74 (dd,J=7.8, 1.0, 1H)

175b)6-cyclopropyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.62 g), sodium hydrogencarbonate (0.89 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(4-cyclopropyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.44 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.19 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.29 g,57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-0.95 (m, 2H), 1.99 (s, 3H), 2.12-2.24(m, 1H), 2.47-2.53 (m, 2H), 3.99 (s, 2H), 7.21-7.26 (m, 2H), 7.31-7.38(m, 4H), 7.47-7.58 (m, 5H), 7.63-7.73 (m, 2H), 12.41 (s, 1H)

Example 1766-ethyl-3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

176a)4′-{[4-ethyl-1-(4-isopropoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-ethyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.99 g), (4-isopropoxyphenyl)boronic acid (1.08 g), molecular sieves 4A (0.49 g), triethylamine (2.1 mL), pyridine (1.0 mL), copper(II)acetate (1.09 g) and methylene chloride (20 mL) was stirred at roomtemperature for 24 hr. Ethyl acetate was added to the reaction mixture,and the insoluble solid was filtered off. The solvent of the filtratewas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.68 g, 49%).

¹H NMR (300 MHz, CDCl₃) δ 1.14 (t, J=7.5, 3H), 2.69 (d, J=6.0 Hz, 6H),2.14 (s, 3H), 2.58 (d, J=7.5, 2H), 3.92 (s, 2H), 4.66-4.78 (m, 1H),7.08-7.14 (m, 2H), 7.25-7.38 (m, 6H), 7.49-7.53 (m, 1H), 7.62 (dd,J=7.5, 1.3, 1H), 7.68-7.77 (m, 2H)

176b)6-ethyl-3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.86 g), sodium hydrogencarbonate (1.23 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-1-(4-isopropoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.68 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.26 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.62 g,81%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.07 (t, J=7.5, 3H), 1.30 (d, J=6.0 Hz, 6H),2.07 (s, 3H), 2.54 (d, J=7.5, 2H), 3.87 (s, 2H), 4.61-4.73 (m, 1H),7.01-7.06 (m, 2H), 7.20-7.31 (m, 6H), 7.49-7.53 (m, 1H), 7.56 (dd,J=7.5, 1.3, 1H), 7.63-7.71 (m, 2H), 12.37 (s, 1H)

Example 1776-cyclopropyl-3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

177a)4′-{[4-cyclopropyl-1-(4-isopropoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-cyclopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.02 g), (4-isopropoxyphenyl)boronic acid (1.08 g), molecular sieves 4A (0.51 g), triethylamine (2.1 mL), pyridine (1.0 mL), copper(II)acetate (1.09 g) and methylene chloride (20 mL) was stirred at roomtemperature for 24 hr. Ethyl acetate was added to the reaction mixture,and the insoluble solid was filtered off. The solvent of the filtratewas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.39 g, 27%).

¹H NMR (300 MHz, CDCl₃) δ 0.88-0.98 (m, 2H), 1.02-1.13 (m, 2H), 1.73 (d,J=6.0, 6H), 2.12-2.25 (m, 1H), 2.49-2.59 (m, 3H), 4.02 (s, 2H),4.67-4.81 (m, 1H), 7.01-7.08 (m, 2H), 7.28-7.38 (m, 4H), 7.39-7.44 (m,2H), 7.49-7.55 (m, 2H), 7.66-7.72 (m, 2H)

177b)6-cyclopropyl-3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.48 g), sodium hydrogencarbonate (0.69 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-cyclopropyl-1-(4-isopropoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.39 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.13 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.28 g,64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-0.94 (m, 2H), 0.99-1.05 (m, 2H), 1.29(d, J=6.0, 6H), 2.11-2.22 (m, 1H), 2.45-2.53 (m, 3H), 3.98 (s, 2H),4.61-4.72 (m, 1H), 6.98-7.05 (m, 2H), 7.18-7.26 (m, 4H), 7.29-7.36 (m,2H), 7.49-7.58 (m, 2H), 7.63-7.72 (m, 2H), 12.40 (s, 1H)

Example 1783-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

178a)4′-[(6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To an ice-cooled mixture of formamidine hydrochloride (3.73 g) andmethanol (25 mL) was added dropwise 28% sodium methoxide-methanolsolution (13.7 mL), and a mixture of methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate (5.90 g), 1,4-dioxane(18 mL) and methanol (25 mL) was added dropwise. The mixture was stirredat room temperature for 12 hr. The solvent of the reaction mixture wasevaporated under reduced pressure. The residue was diluted with ethylacetate, and the diluted solution was washed with 0.1 M aqueoushydrochloric acid solution, water and saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure to give crude crystals. The crude crystals were washed withdiisopropyl ether to give the title compound as a colorless solid (3.40g, 61%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.2, 3H), 1.58-1.72 (m, 2H),2.57-2.67 (m, 2H), 4.01 (s, 2H), 7.32-7.37 (m, 2H), 7.38-7.44 (m, 1H),7.45-7.51 (m, 3H), 7.62 (td, J=7.6, 1.1, 1H), 7.74 (dd, J=7.2, 0.8, 1H),8.07 (s, 1H), 12.77-13.31 (m, 1H)

178b)4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.02 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.78g), molecular sieves 4 A (1.98 g), triethylamine (1.7 mL), pyridine (1.0mL), copper(II) acetate (0.65 g) and methylene chloride (15 mL) wasstirred at room temperature for 24 hr. Ethyl acetate was added to thereaction mixture, and the insoluble solid was filtered off. The solventof the filtrate was evaporated under reduced pressure, and the residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (0.76 g, 54%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.49 (s, 6H), 1.64-1.78(m, 2H), 2.65-2.74 (m, 2H), 3.06 (s, 2H), 4.02 (s, 2H), 6.80 (d, J=8.3,1H), 7.06 (dd, J=8.5, 2.5, 1H), 7.15-7.19 (m, 1H), 7.37-7.51 (m, 6H),7.61 (td, J=7.7, 1.3, 1H), 7.74 (dd, J=8.0, 1.1, 1H), 8.08 (s, 1H)

178c)3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogencarbonate (1.35 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min,4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.76 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.29 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.46 g,53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4, 3H), 1.44 (s, 6H), 1.49-1.67(m, 2H), 2.52-2.59 (m, 2H), 3.06 (s, 2H), 3.92 (s, 2H), 6.81 (d, J=8.5,1H), 7.14-7.32 (m, 6H), 7.48-7.58 (m, 2H), 7.63-7.72 (m, 2H), 8.28 (s,1H), 12.38 (s, 1H)

3-(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 1793-(4-isopropoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

179a)4′-{[1-(4-isopropoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.02 g), (4-isopropoxyphenyl)boronic acid (0.65 g), molecular sieves 4A (1.98 g), triethylamine (1.7 mL), pyridine (1.0 mL), copper(II)acetate (0.65 g) and methylene chloride (15 mL) was stirred at roomtemperature for 24 hr. Ethyl acetate was added to the reaction mixture,and the insoluble solid was filtered off. The solvent of the filtratewas evaporated under reduced pressure, and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.62 g, 44%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.2, 3H), 1.35 (d, J=6.0, 6H),1.64-1.78 (m, 2H), 2.66-2.73 (m, 2H), 4.02 (s, 2H), 4.51-4.65 (m, 1H),6.94-7.00 (m, 2H), 7.25-7.31 (m, 2H), 7.37-7.50 (m, 6H), 7.61 (td,J=7.7, 1.3, 1H), 7.73 (dd, J=7.8, 1.0, 1H), 8.08 (s, 1H)

179b)3-(4-isopropoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.79 g), sodium hydrogencarbonate (1.12 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-isopropoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.62 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.30 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.58 g,83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4, 3H), 1.29 (d, J=6.0 Hz, 6H),1.49-1.64 (m, 2H), 2.48-2.52 (m, 1H), 2.52-2.61 (m, 2H), 3.92 (s, 2H),7.00-7.08 (m, 2H), 7.21-7.25 (m, 2H), 7.28-7.33 (m, 2H), 7.34-7.41 (m,2H), 7.47-7.58 (m, 2H), 7.63-7.72 (m, 2H), 8.30 (s, 1H), 12.38 (s, 1H)

Example 1803-(4′-{[3-butyl-5-oxo-1-(2-phenylethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

180a)4′-{[3-butyl-5-oxo-1-(2-phenylethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(1.00 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride(0.60 g), and the mixture was stirred at room temperature for 30 min. Tothe mixture was added (2-bromoethyl)benzene (2.22 g), and the mixturewas stirred at room temperature for 4 hr. The reaction mixture wasdiluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.72 g, 55%).

¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, J=7.4, 3H), 1.28-1.44 (m, 2H),1.56-1.62 (m, 2H), 2.41-2.48 (m, 2H), 3.10 (t, J=7.4, 2H), 4.04 (m, 2H),4.72 (s, 2H), 7.17 (d, J=8.3, 2H), 7.20-7.28 (m, 2H), 7.29-7.41 (m, 5H),7.44 (dd, J=7.5, 1.13, 1H), 7.47-7.58 (m, 1H), 7.66-7.73 (m, 1H), 7.81(dd, J=7.6, 1.2, 1H)

180b)3-(4′-{[3-butyl-5-oxo-1-(2-phenylethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogencarbonate (1.38 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[3-butyl-5-oxo-1-(2-phenylethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile(0.72 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.45 g,55%).

¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, J=7.4, 3H), 1.24-1.40 (m, 2H),1.49-1.62 (m, 2H), 2.35-2.43 (m, 2H), 3.02 (t, J=7.4, 2H), 3.91-3.99 (m,2H), 4.72 (s, 2H), 7.10 (d, J=8.3, 2H), 7.14-7.18 (m, 2H), 7.19-7.32 (m,5H), 7.41 (dd, J=7.5, 1.1, 1H), 7.49 (td, J=7.6, 1.2, 1H), 7.61 (td,J=7.6, 1.3, 1H), 7.77 (dd, J=7.6, 1.2, 1H), 12.40 (s, 1H)

Example 1813-{4′-[(3-butyl-1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-yl}-1,2,4-oxadiazol-5(4H)-one

181a)4′-[(3-butyl-1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile

To a mixture of4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(1.00 g) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride(0.60 g), and the mixture was stirred at room temperature for 30 min.

To the mixture was added 2-bromobutane (1.64 g), and the mixture wasstirred at room temperature for 5 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.61 g,53%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.4, 3H), 1.07 (t, J=7.3, 3H), 1.36(d, J=6.8, 3H), 1.33-1.45 (m, 2H), 1.54-1.67 (m, 2H), 1.70-1.81 (m, 2H),2.41-2.55 (m, 2H), 3.99-4.20 (m, 1H), 4.81 (s, 2H), 7.23-7.34 (m, 2H),7.35-7.41 (m, 2H), 7.50 (dd, J=7.7, 0.94, 1H), 7.54 (dt, J=7.6, 1.32,1H), 7.70 (dt, J=7.6, 1.4, 1H), 7.91 (dd, J=7.7, 1.1, 1H)

181b)3-{4′-[(3-butyl-1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-yl}-1,2,4-oxadiazol-5(4H)-one

A mixture of hydroxylammonium chloride (0.93 g), sodium hydrogencarbonate (1.33 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(3-butyl-1-sec-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(0.61 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.10 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.14 g,20%).

¹H NMR (300 MHz, CDCl₃) δ 0.77 (t, J=7.4, 3H), 0.87 (t, J=7.3, 3H), 1.27(d, J=6.8, 3H), 1.30-1.39 (m, 2H), 1.48-1.65 (m, 2H), 1.67-1.81 (m, 2H),2.37-2.45 (m, 2H), 3.96-4.10 (m, 1H), 4.75 (s, 2H), 7.17-7.21 (m, 2H),7.30-7.34 (m, 2H), 7.42 (dd, J=7.7, 0.9, 1H), 7.49 (td, J=7.6, 1.3, 1H),7.61 (td, J=7.6, 1.4, 1H), 7.74 (dd, J=7.7, 1.1, 1H), 12.38 (s, 1H)

Example 1823-{4′-[(3-butyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-yl}-1,2,4-oxadiazol-5(4H)-one

182a)4′-[(3-butyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(1.80 g), phenylboronic acid (1.98 g), molecular sieves 4 A (0.90 g),triethylamine (3.8 mL), pyridine (1.8 mL), copper(II) acetate (1.97 g)and methylene chloride (120 mL) was stirred at room temperature for 24hr. Ethyl acetate was added to the reaction mixture, and the insolublesolid was filtered off. The solvent of the filtrate was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.26 g,57%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.5, 3H), 1.31-1.47 (m, 2H),1.59-1.75 (m, 2H), 2.53-2.60 (m, 2H), 5.07 (s, 2H), 7.33 (t, J=7.4, 1H),7.42 (s, 4H), 7.43-7.51 (m, 3H), 7.56 (d, J=6.8, 1H), 7.66-7.71 (m, 2H),7.96 (d, J=7.7, 2H)

182b)3-{4′-[(3-butyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-yl}-1,2,4-oxadiazol-5(4H)-one

A mixture of hydroxylammonium chloride (3.20 g), sodium hydrogencarbonate (4.55 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min,4′-[(3-butyl-5-oxo-1-phenyl-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(1.26 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (30 mL), N,N′-carbonyldiimidazole (0.58 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.54 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.85 g,34%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.4, 3H), 1.26-1.41 (m, 2H),1.49-1.62 (m, 2H), 2.53-2.60 (m, 2H), 4.97 (s, 2H), 7.22 (t, J=7.4, 1H),7.33 (s, 4H), 7.43-7.51 (m, 3H), 7.54 (d, J=6.8, 1H), 7.62-7.68 (m, 2H),7.94 (d, J=7.7, 2H), 12.39 (s, 1H)

Example 1833-(4′-{[3-butyl-5-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

183a)4′-{[3-butyl-5-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(1.13 g), potassium carbonate (0.94 g),2-(bromomethyl)tetrahydro-2H-pyran (0.90 g) and N,N-dimethylformamide(20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.55 g,38%).

¹H NMR (300 MHz, CDCl₃) δ 0.87 (t, J=7.4, 3H), 1.20-1.40 (m, 4H),1.46-1.68 (m, 5H), 1.85 (dd, J=6.8, 3.0, 1H), 2.40-2.47 (m, 2H), 3.40(td, J=11.3, 2.1, 1H), 3.70-3.79 (m, 2H), 3.89-4.03 (m, 2H), 4.90 (s,2H), 7.35-7.41 (m, 2H), 7.41-7.58 (m, 4H), 7.65 (td, J=7.7, 1.3, 1H),7.75 (dd, J=7.8, 1.0, 1H)

183b)3-(4′-{[3-butyl-5-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

A mixture of hydroxylammonium chloride (0.76 g), sodium hydrogencarbonate (1.08 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[3-butyl-5-oxo-1-(tetrahydro-2H-pyran-2-ylmethyl)-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile(0.55 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.31 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.33 g,53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (t, J=7.3, 3H), 1.15-1.34 (m, 3H),1.36-1.50 (m, 4H), 1.52-1.61 (m, 1H), 1.72-1.81 (m, 1H), 2.39-2.46 (m,2H), 3.22-3.34 (m, 2H), 3.52-3.65 (m, 2H), 3.70-3.87 (m, 2H), 4.86 (s,2H), 7.17-7.34 (m, 4H), 7.50-7.55 (m, 1H), 7.58 (dd, J=7.4, 1.2, 1H),7.62-7.74 (m, 2H), 12.41 (s, 1H)

Example 1845-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-6-propylpyrimidin-4(3H)-one

184a)4′-{[1-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.04 g), 1-bromo-3,3-dimethylbutan-2-one (1.53 g), potassium carbonate(1.59 g) and N,N-dimethylformamide (30 mL) was stirred at roomtemperature for 4 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.67 g,26%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (t, J=7.4, 3H), 1.28 (s, 9H), 1.56-1.70(m, 2H), 2.33 (s, 3H), 2.50-2.57 (m, 2H), 3.96 (s, 2H), 5.09 (s, 2H),7.19-7.27 (m, 3H), 7.37-7.47 (m, 2H), 7.60 (t, J=7.6, 1H), 7.71 (d,J=7.6, 1H)

184b)5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of4′-{[1-(3,3-dimethyl-2-oxobutyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.67 g), sodium borohydride (0.17 g) and methanol was stirred at roomtemperature for 12 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. A mixture of hydroxylammonium chloride (0.76 g), sodiumhydrogen carbonate (1.08 g) and dimethyl sulfoxide (10 mL) was stirredat 40° C. for 30 min, the concentrate was added, and the mixture wasstirred at 90° C. for 16 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (15 mL),N,N′-carbonyldiimidazole (0.31 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.51 g,67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.2, 3H), 0.93 (s, 9H), 1.43-1.57(m, 2H), 2.38-2.45 (m, 2H), 2.56 (s, 3H), 3.41-3.50 (m, 1H), 3.64 (dd,J=13.1, 10.4, 1H), 3.76-3.91 (m, 2H), 4.23 (d, J=12.1, 2H), 5.02 (d,J=5.7, 1H), 6.99 (dd, J=8.0, 1.14, 1H), 7.06-7.17 (m, 2H), 7.53 (d,J=8.0, 1H), 7.59 (d, J=7.2, 1H), 7.65-7.73 (m, 2H), 12.44 (s, 1H)

Example 185

3-(3,3-dimethyl-2-oxobutyl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2-hydroxy-3,3-dimethylbutyl)-2-methyl-6-propylpyrimidin-4(3H)-one(0.28 g), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.34 g) and methylene chloride (15 mL) was stirred at room temperaturefor 2 hr. Saturated aqueous sodium hydrogen carbonate and sodiumthiosulfate pentahydrate were added to the reaction mixture, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with chloroform, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as colorlesscrystals (0.15 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.4, 3H), 1.21 (s, 9H), 1.46-1.59(m, 2H), 2.29 (s, 3H), 2.42-2.49 (m, 2H), 3.83 (s, 2H), 5.16 (s, 2H),6.98-7.09 (m, 2H), 7.13 (dd, J=11.0, 1.5, 1H), 7.51-7.61 (m, 2H),7.65-7.73 (m, 2H), 12.44 (s, 1H)

Example 1866-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

186a)4′-[(4-butyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), phenylboronic acid (1.02 g), triethylamine (1.95 mL), pyridine(1.13 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL)was added copper(II) acetate (1.02 g), and the mixture was stirred for 2days. The reaction mixture was diluted with ethyl acetate. The insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.28 g, 23%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.33-1.71 (m, 4H), 2.16(s, 3H), 2.57-2.75 (m, 2H), 3.97 (s, 2H), 7.19-7.81 (m, 13H)

186b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.36 g), sodium hydrogencarbonate (0.55 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-[(4-butyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.28 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.11g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.104 mL) were added,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.13 g, 41%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.3, 3H), 1.35-1.79 (m, 4H), 2.11(s, 3H), 2.62-2.76 (m, 2H), 3.87 (s, 2H), 7.11-7.76 (m, 14H)

Example 1876-butyl-2-methyl-3-(4-methylphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

187a)4′-{[4-butyl-2-methyl-1-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 4-methylphenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in tetrahydrofuran(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.98 g, 78%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.3, 3H), 1.31-1.77 (m, 4H), 2.17(s, 3H), 2.41 (s, 3H), 2.56-2.76 (m, 2H), 3.97 (s, 2H), 7.02-7.81 (m,12H)

187b)6-butyl-2-methyl-3-(4-methylphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(4-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.98 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.45g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.77 g, 70%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.3, 3H), 1.32-1.84 (m, 4H), 2.13(s, 3H), 2.39 (s, 3H), 2.62-2.79 (m, 2H), 3.89 (s, 2H), 6.85-7.94 (m,13H)

Example 1886-butyl-2-methyl-3-(3-methylphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

188a)4′-{[4-butyl-2-methyl-1-(3-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 3-methylphenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.29 g, 99%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.3, 3H), 1.33-1.72 (m, 4H), 2.17(s, 3H), 2.40 (s, 3H), 2.61-2.74 (m, 2H), 3.97 (s, 2H), 6.98-7.78 (m,12H)

188b)6-butyl-2-methyl-3-(3-methylphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.4 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(3-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.29 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.52g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.48 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.88 g, 60%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.36-1.82 (m, 4H), 2.10(s, 3H), 2.34 (s, 3H), 2.58-2.75 (m, 2H), 3.86 (s, 2H), 6.82-7.88 (m,12H), 8.49-9.32 (m, 1H)

Example 1896-butyl-3-(3-isopropylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

189a)4′-{[4-butyl-1-(3-isopropylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 3-isopropylphenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.04 g, 78%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.3, 3H), 1.27 (dd, J=6.9, 1.6,6H), 1.34-1.70 (m, 4H), 2.15 (s, 3H), 2.57-2.74 (m, 2H), 2.87-3.06 (m,1H), 3.91-4.05 (m, 2H), 7.00-7.79 (m, 12H)

189b)6-butyl-3-(3-isopropylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-isopropylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.04 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.41g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.66 g, 57%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.22 (d, J=4.1, 3H), 1.24(d, J=4.1, 3H), 1.36-1.75 (m, 4H), 2.11 (s, 3H), 2.63-2.72 (m, 2H),2.84-3.02 (m, 1H), 3.80-3.94 (m, 2H), 6.90-7.75 (m, 12H), 9.09 (s, 1H)

Example 1906-butyl-3-(3-chlorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

190a)4′-{[4-butyl-1-(3-chlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 3-chlorophenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate,the insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.96 g, 73%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.35-1.70 (m, 4H), 2.18(s, 3H), 2.61-2.73 (m, 2H), 3.96 (s, 2H), 7.10-7.78 (m, 12H)

190b)6-butyl-3-(3-chlorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-chlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.96 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.41g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.65 g, 60%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.33-1.80 (m, 4H), 2.13(s, 3H), 2.60-2.84 (m, 2H), 3.76-3.99 (m, 2H), 6.95-7.84 (m, 12H), 8.90(s, 1H)

Example 1916-butyl-3-(3-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

191a)4′-{[4-butyl-1-(3-methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 3-methoxyphenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.43 g, 33%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.31-1.75 (m, 4H), 2.19(s, 3H), 2.56-2.78 (m, 2H), 3.83 (s, 3H), 3.97 (s, 2H), 6.70-7.84 (m,12H)

191b)6-butyl-3-(3-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogencarbonate (0.77 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.43 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the aqueous layer was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was evaporated. Theresidue was dissolved in tetrahydrofuran (10 mL),N,N′-carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.23 g, 47%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.33-1.77 (m, 4H), 2.13(s, 3H), 2.58-2.75 (m, 2H), 3.77 (s, 3H), 3.87 (s, 2H), 6.63-7.74 (m,12H), 8.71 (s, 1H)

Example 1926-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

192a)4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (1.0 g),triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g),and the mixture was stirred for 2 days. The reaction mixture was dilutedwith ethyl acetate. The insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (1.20 g, 90%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.3, 3H), 1.33-1.71 (m, 4H), 2.20(s, 3H), 2.56-2.75 (m, 2H), 3.15-3.36 (m, 2H), 3.86-4.04 (m, 2H),4.54-4.75 (m, 2H), 6.83-7.79 (m, 11H)

192b)6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (2.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.56g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.74 g, 55%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.33-1.72 (m, 4H), 2.10(s, 3H), 2.53-2.74 (m, 2H), 3.18 (t, J=8.8, 2H), 3.74-3.92 (m, 2H), 4.62(t, J=8.8, 2H), 6.62-7.73 (m, 11H), 9.18 (s, 1H)

Example 1936-butyl-2-methyl-3-(2-methylphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

193a)4′-{[4-butyl-2-methyl-1-(2-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 2-methylphenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.12 g, 10%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.31-1.78 (m, 4H), 2.09(s, 3H), 2.10 (s, 3H), 2.62-2.72 (m, 2H), 3.99 (s, 2H), 7.07-7.80 (m,12H)

193b)6-butyl-2-methyl-3-(2-methylphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.30 g), sodium hydrogencarbonate (0.45 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(2-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (4 mL), N,N′-carbonyldiimidazole (0.086g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.079 mL) were added,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.11 g, 42%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.30-1.77 (m, 4H), 1.95(s, 3H), 2.03 (s, 3H), 2.59-2.70 (m, 2H), 3.81-3.96 (m, 2H), 6.96-7.74(m, 12H), 8.74 (s, 1H)

Example 1946-butyl-3-(3,5-dichlorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

194a)4′-{[4-butyl-1-(3,5-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (3,5-dichlorophenyl)boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylenechloride (15 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred for 2 days. The reaction mixture was diluted with ethylacetate, the insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.49 g, 35%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.3, 3H), 1.31-1.70 (m, 4H), 2.20(s, 3H), 2.61-2.73 (m, 2H), 3.95 (s, 2H), 7.17-7.79 (m, 11H)

194b)6-butyl-3-(3,5-dichlorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.82 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3,5-dichlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.49 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (1 mL), N,N′-carbonyldiimidazole (0.018g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.016 mL) were added,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.029 g, 5%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.35-1.75 (m, 4H), 2.16(s, 3H), 2.63-2.76 (m, 2H), 3.88 (s, 2H), 7.08-7.83 (m, 12H)

Example 1956-butyl-3-(4-chlorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

195a)4′-{[4-butyl-1-(4-chlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 4-chlorophenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate,the insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.68 g, 52%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.30-1.75 (m, 4H), 2.17(s, 3H), 2.52-2.78 (m, 2H), 3.96 (s, 2H), 7.03-7.91 (m, 12H)

195b)6-butyl-3-(4-chlorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.81 g), sodium hydrogencarbonate (1.23 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-chlorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.68 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.28g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.42 g, 55%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.33-1.77 (m, 4H), 2.11(s, 3H), 2.56-2.76 (m, 2H), 3.85 (s, 2H), 6.87-7.91 (m, 12H), 8.69 (s,1H)

Example 1966-butyl-2-methyl-3-(2-naphthyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

196a)4′-{[4-butyl-2-methyl-1-(2-naphthyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 2-naphthylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate,the insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.13 g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.34-1.73 (m, 4H), 2.20(s, 3H), 2.61-2.82 (m, 2H), 3.90-4.09 (m, 2H), 7.29-8.07 (m, 15H)

196b)6-butyl-2-methyl-3-(2-naphthyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.30 g), sodium hydrogencarbonate (1.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(2-naphthyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.13 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.46g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.89 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84-0.90 (m, 3H), 1.25-1.60 (m, 4H), 2.10(s, 3H), 2.53-2.61 (m, 2H), 3.90 (s, 2H), 7.17-8.14 (m, 15H), 12.40 (s,1H)

Example 1976-butyl-3-[3-(2-hydroxyethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

197a)4′-{[4-butyl-1-(3-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(5.0 g), (3-{[tert-butyl(dimethyl)silyl]oxy}phenyl)boronic acid (9.0 g),triethylamine (10.0 mL), pyridine (5.0 mL) and molecular sieves 4 A(10.0 g) in methylene chloride (100 mL) was added copper(II) acetate(5.0 g), and the mixture was stirred for 2 days. The reaction mixturewas diluted with ethyl acetate. The insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue wasdissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (1.7g) was added, and the mixture was stirred for 15 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate, and the solvent wasevaporated. The residue was purified by silica gel column chromatographyto give the title compound as a pale-yellow viscous substance (1.71 g,21%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (t, J=7.3, 3H), 1.30-1.71 (m, 4H), 2.16(s, 3H), 2.50-2.74 (m, 2H), 4.02 (q, J=15.0, 2H), 6.37-8.08 (m, 13H)

197b)4′-({4-butyl-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[4-butyl-1-(3-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and (2-bromoethoxy)(tert-butyl)dimethylsilane (0.95 mL) inN,N-dimethylformamide (10 mL) was added cesium carbonate (1.45 g), andthe mixture was stirred at 60° C. for 15 hr. The reaction mixture wasallowed to cool to room temperature, ethyl acetate and water were added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was evaporated. The residue was purified by silica gelcolumn chromatography to give the title compound as a pale-yellowviscous substance (1.13 g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 0.10 (s, 6H), 0.90 (s, 9H), 0.95 (t, J=7.3,3H), 1.33-1.72 (m, 4H), 2.19 (s, 3H), 2.61-2.71 (m, 2H), 3.92-4.17 (m,6H), 6.70-7.79 (m, 12H)

197c)6-butyl-3-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.03 g), sodium hydrogencarbonate (1.55 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.13 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.45g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.95 g, 77%).

¹H NMR (300 MHz, CDCl₃) δ 0.09 (s, 6H), 0.90 (s, 9H), 0.96 (t, J=7.2,3H), 1.36-1.74 (m, 4H), 2.14 (s, 3H), 2.62-2.72 (m, 2H), 3.83-4.04 (m,6H), 6.64-7.78 (m, 12H), 8.65 (s, 1H)

197d)6-butyl-3-[3-(2-hydroxyethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of6-butyl-3-[3-(2-{[tert-butyl(dimethyl)silyl]oxy}ethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.95 g) in tetrahydrofuran (7 mL) was added tetrabutylammonium fluoride(0.56 g), and the mixture was stirred at 50° C. for 12 hr. The reactionmixture was allowed to cool to room temperature, ethyl acetate and waterwere added, and the aqueous layer was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was evaporated. The residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.55 g, 70%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.4, 3H), 1.35-1.80 (m, 4H), 2.15(s, 3H), 2.45-2.82 (m, 3H), 3.73-4.07 (m, 6H), 6.57-7.84 (m, 12H), 9.10(s, 1H)

Example 198

2-{[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]methyl}benzoicacid

A mixture of methyl2-{[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]methyl}benzoate(0.28 g), 2 N aqueous sodium hydroxide solution (5 mL) and methanol (5mL) was stirred at 50° C. for 3 hr. The reaction mixture was adjusted topH 4 with water (20 mL) and 1 M hydrochloric acid, and the obtainedcrystallized product was collected by filtration to give the titlecompound as colorless crystals (0.22 g, 80%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.3), 1.44-1.63 (2H, m), 2.33(3H, s), 2.49-2.56 (2H, m), 3.89 (2H, s), 5.61 (2H, s), 6.66 (1H, d,J=7.7), 7.22 (4H, s), 7.36-7.56 (4H, m), 7.63 (2H, dd, J=7.3, 2.8), 7.99(1H, d, J=7.5), 12.88 (2H, br)

Example 1996-butyl-3-[3-(1-hydroxyethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

199a)4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(5.0 g), (3-acetylphenyl)boronic acid (5.0 g), triethylamine (10.0 mL),pyridine (5.0 mL) and molecular sieves 4 A (10.0 g) in methylenechloride (100 mL) was added copper(II) acetate (5.0 g), and the mixturewas stirred for 2 days. The reaction mixture was diluted with ethylacetate. The insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (2.20 g, 33%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.35-1.74 (m, 4H), 2.17(s, 3H), 2.63 (s, 3H), 2.64-2.73 (m, 2H), 3.97 (s, 2H), 7.29-8.12 (m,12H)

199b)4′-({4-butyl-1-[3-(1-hydroxyethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.20 g) in ethanol (20 mL) was added sodium tetrahydroboron (0.18 g),and the mixture was stirred for 3 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was evaporated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (1.86 g, 84%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.33-1.72 (m, 7H),2.06-2.22 (m, 4H), 2.60-2.74 (m, 2H), 3.97 (s, 2H), 4.84-5.02 (m, 1H),7.08-7.78 (m, 12H)

199c)4′-({4-butyl-1-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({4-butyl-1-[3-(1-hydroxyethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.86 g), triethylamine (1.1 mL) and 4-dimethylaminopyridine (0.15 g) inN,N-dimethylformamide (20 mL) was added tert-butyl(chloro)dimethylsilane(0.88 g), and the mixture was stirred for 15 hr. Ethyl acetate and waterwere added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate, and the solvent was evaporated.The residue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (1.98 g, 86%).

¹H NMR (300 MHz, CDCl₃) δ −0.02 (d, J=7.9, 3H), 0.06 (d, J=9.4, 3H),0.89 (d, J=5.3, 9H), 0.95 (t, J=7.3, 3H), 1.35-1.71 (m, 7H), 2.14 (d,J=3.2, 3H), 2.60-2.72 (m, 2H), 3.89-4.06 (m, 2H), 4.80-5.00 (m, 1H),7.01-7.83 (m, 12H)

199d)6-butyl-3-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.86 g), sodium hydrogencarbonate (2.81 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.98 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.82g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.77 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (1.70 g, 78%).

¹H NMR (300 MHz, CDCl₃) δ −0.04 (d, J=9.1, 3H), 0.05 (d, J=9.1, 3H),0.88 (d, J=4.5, 9H), 0.96 (t, J=7.2, 3H), 1.35-1.75 (m, 7H), 2.10 (s,3H), 2.61-2.73 (m, 2H), 3.80-3.97 (m, 2H), 4.79-4.97 (m, 1H), 6.93-7.77(m, 12H), 8.71 (s, 1H)

199e)6-butyl-3-[3-(1-hydroxyethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of6-butyl-3-[3-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(1.70 g) in tetrahydrofuran (10 mL) was added tetrabutylammoniumfluoride (1.0 g), and the mixture was stirred at 50° C. for 12 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (0.88 g, 63%).

¹H NMR (300 MHz, CDCl₃) δ 0.98 (t, J=7.4, 3H), 1.38-1.80 (m, 7H), 2.13(d, J=10.6, 3H), 2.67-2.78 (m, 2H), 2.99-3.48 (m, 1H), 3.75-3.95 (m,2H), 4.76-4.90 (m, 1H), 6.92-7.78 (m, 12H), 9.32 (s, 1H)

Example 2003-[4′-({3-butyl-1-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-yl]-1,2,4-oxadiazol-5(4H)-one

200a)4′-({3-butyl-1-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(0.7 g), potassium tert-butoxide (1.0 M tetrahydrofuran solution, 1.75mL) and N,N-dimethylformamide (10 mL) was stirred at room temperaturefor 10 min, 2-bromo-1-(4-fluorophenyl)ethanone (0.35 g) was added, andthe mixture was stirred at room temperature for 16 hr. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.6 g,88%).

¹H NMR (300 MHz, CDCl₃) δ 0.87 (3H, t, J=7.3), 1.28-1.41 (2H, m),1.53-1.67 (2H, m), 2.40-2.50 (2H, m), 4.95 (2H, s), 5.24 (2H, s),7.13-7.22 (2H, m), 7.39 (2H, d, J=8.1), 7.43-7.52 (2H, m), 7.57 (2H, d,J=8.1), 7.65 (1H, dd, J=7.6, 1.2), 7.74-7.80 (1H, m), 7.97-8.08 (2H, m)

200b)3-[4′-({3-butyl-1-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-yl]-1,2,4-oxadiazol-5(4H)-one

A mixture of hydroxylammonium chloride (1.07 g), sodium hydrogencarbonate (1.61 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-({3-butyl-1-[2-(4-fluorophenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-carbonitrile(0.6 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (20 mL), N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.2 g,29%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79 (3H, t, J=7.3), 1.21-1.33 (2H, m),1.36-1.55 (2H, m), 2.41-2.49 (2H, m), 4.93 (2H, s), 5.37 (2H, s),7.27-7.37 (4H, m), 7.41 (2H, t, J=8.8), 7.51-7.64 (2H, m), 7.64-7.77(2H, m), 8.12 (2H, dd, J=8.6, 5.6), 12.42 (1H, s)

Example 201

3-(3-acetylphenyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of6-butyl-3-[3-(1-hydroxyethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.3 g) in acetonitrile (3 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.36 g),and the mixture was stirred for 2 hr. To the reaction mixture were addedethyl acetate, water and sodium thiosulfate, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.21 g,71%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.4, 3H), 1.36-1.78 (m, 4H), 2.13(s, 3H), 2.60 (s, 3H), 2.66-2.77 (m, 2H), 3.90 (s, 2H), 7.13-8.08 (m,12H), 8.30 (s, 1H)

Example 2026-butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

202a)4′-{[4-butyl-1-(3,4-dimethylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 3,4-dimethylphenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.27 g, 98%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.2, 3H), 1.34-1.68 (m, 4H), 2.17(s, 3H), 2.30 (d, J=2.7, 6H), 2.59-2.71 (m, 2H), 3.96 (s, 2H), 6.82-7.83(m, 11H)

202b)6-butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogencarbonate (2.50 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3,4-dimethylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.27 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.65g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (1.01 g, 71%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.2, 3H), 1.29-1.76 (m, 4H), 2.07(s, 3H), 2.22 (s, 3H), 2.28 (s, 3H), 2.55-2.69 (m, 2H), 3.83 (s, 2H),6.68-7.66 (m, 11H), 9.25 (s, 1H)

6-Butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(3,4-dimethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 2036-butyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-one

203a) methyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate

To a solution of methyl 3-oxoheptanoate (10.9 g) in tetrahydrofuran (100mL) was added 60% sodium hydride (2.07 g), and the mixture was stirredfor 1 hr. A solution of4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (10.0 g) intetrahydrofuran (50 mL) was added, and the mixture was stirred for 15hr. Ammonium chloride and water were added to the reaction mixture, andthe mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was evaporated. The residue was purified by silica gelcolumn chromatography to give the title compound as a pale-yellowviscous substance (13.0 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.77-0.96 (m, 3H), 1.15-1.38 (m, 2H),1.43-1.64 (m, 2H), 2.33-2.73 (m, 2H), 3.24 (d, J=7.3, 2H), 3.71 (s, 3H),3.93 (t, J=7.4 Hz, 1H), 7.11-7.93 (m, 7H)

203b)4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile

To a suspension of acetamidine hydrochloride (6.7 g) in methanol (50 mL)were added sodium methoxide (28% methanol solution, 20.5 mL) and thenmethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxoheptanoate (13.0g), and the mixture was stirred for 15 hr. Water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate, and the solvent was evaporated. The residue wastriturated with diisopropyl ether to give the title compound (9.15 g,69%) as pale-yellow crystals.

¹H NMR (300 MHz, CDCl₃) δ 0.89 (t, J=7.2, 3H), 1.25-1.63 (m, 4H), 2.42(s, 3H), 2.52-2.68 (m, 2H), 3.98 (s, 2H), 7.11-7.82 (m, 7H), 13.28 (s,1H)

203c)4′-[(4-butyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(1.0 g), phenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine(1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL)was added copper(II) acetate (1.0 g), and the mixture was stirred for 2days. The reaction mixture was diluted with ethyl acetate. The insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.28 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, 3H), 1.32-1.71 (m, 4H), 2.17 (s, 3H),2.58-2.75 (m, 2H), 3.99 (s, 2H), 7.16-7.78 (m, 12H)

203d)6-butyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogencarbonate (2.50 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(4-butyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(1.28 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.65g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.84 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.2, 3H), 1.31-1.74 (m, 4H), 2.10(s, 3H), 2.56-2.82 (m, 2H), 3.87 (s, 2H), 6.77-7.70 (m, 12H), 9.37 (s,1H)

Example 2046-butyl-5-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-one

204a) methyl2-[(2′-cyano-3,5-difluorobiphenyl-4-yl)methyl]-3-oxoheptanoate

To a solution of methyl 3-oxoheptanoate (6.82 g) in tetrahydrofuran (75mL) was added 60% sodium hydride (1.29 g), and the mixture was stirredfor 1 hr. A solution of4′-(bromomethyl)-3′,5′-difluorobiphenyl-2-carbonitrile (6.65 g) intetrahydrofuran (25 mL), and the mixture was stirred for 15 hr. Ammoniumchloride and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (7.93 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.88 (t, J=7.3, 3H), 1.20-1.37 (m, 2H),1.48-1.63 (m, 2H), 2.38-2.72 (m, 2H), 3.18-3.36 (m, 2H), 3.72 (s, 3H),3.91 (t, J=7.6, 1H), 6.97-7.89 (m, 6H)

204b)4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile

To a suspension of acetamidine hydrochloride (3.9 g) in methanol (30 mL)were added sodium methoxide (28% methanol solution, 12 mL) and thenmethyl 2-[(2′-cyano-3,5-difluorobiphenyl-4-yl)methyl]-3-oxoheptanoate(7.93 g), and the mixture was stirred for 15 hr. Water was added to thereaction mixture, and the aqueous layer was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was evaporated. Theresidue was triturated with diisopropyl ether to give the title compound(5.11 g, 63%) as pale-yellow crystals.

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.4, 3H), 1.27-1.60 (m, 4H), 2.38(s, 3H), 2.59-2.71 (m, 2H), 3.95 (s, 2H), 6.96-7.81 (m, 6H), 13.23 (s,1H)

204c)4′-[(4-butyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile(1.0 g), phenylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine(1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL)was added copper(II) acetate (1.0 g), and the mixture was stirred for 2days. The reaction mixture was diluted with ethyl acetate. The insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.21 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.79-1.05 (m, 3H), 1.33-1.66 (m, 4H), 2.14 (s,3H), 2.63-2.73 (m, 2H), 4.00 (s, 2H), 6.95-7.86 (m, 11H)

204d)6-butyl-5-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogencarbonate (2.50 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(4-butyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]-3′,5′-difluorobiphenyl-2-carbonitrile(1.21 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.65g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.63 g, 47%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.2, 3H), 1.36-1.74 (m, 4H), 2.13(s, 3H), 2.68-2.82 (m, 2H), 3.91 (s, 2H), 6.66-7.66 (m, 11H), 9.99 (s,1H)

6-Butyl-5-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-5-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-one    sodium salt-   6-butyl-5-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-one    potassium salt-   6-butyl-5-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-5-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-one    hydrochloride-   6-butyl-5-{[3,5-difluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-phenylpyrimidin-4(3H)-one    hydrobromide

Example 2056-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(3-thienyl)pyrimidin-4(3H)-one

205a)4′-{[4-butyl-2-methyl-6-oxo-1-(3-thienyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 3-thienylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine(1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL)was added copper(II) acetate (1.0 g), and the mixture was stirred for 2days. The reaction mixture was diluted with ethyl acetate. The insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.53 g, 43%).

¹H NMR (300 MHz, CDCl₃) δ 0.91-0.97 (m, 3H), 1.33-1.69 (m, 4H), 2.23 (s,3H), 2.59-2.72 (m, 2H), 3.96 (s, 2H), 6.96-7.03 (m, 1H), 7.28-7.31 (m,1H), 7.36-7.78 (m, 9H)

205b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(3-thienyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogencarbonate (1.02 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(3-thienyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.53 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.19g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.33 g, 55%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.4, 3H), 1.34-1.77 (m, 4H), 2.17(s, 3H), 2.62-2.73 (m, 2H), 3.86 (s, 2H), 6.78-7.78 (m, 11H), 8.81 (s,1H)

Example 2066-butyl-3-(3-furyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

206a)4′-{[4-butyl-1-(3-furyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 3-furylboronic acid (1.0 g), triethylamine (2.0 mL), pyridine(1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL)was added copper(II) acetate (1.0 g), and the mixture was stirred for 2days. The reaction mixture was diluted with ethyl acetate. The insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.13 g, 11%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.2, 3H), 1.28-1.76 (m, 4H), 2.32(s, 3H), 2.49-2.77 (m, 2H), 3.95 (s, 2H), 6.46 (s, 1H), 7.31-7.82 (m,10H)

206b)6-butyl-3-(3-furyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.31 g), sodium hydrogencarbonate (0.50 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-furyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.13 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.073g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.067 mL) were added,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.067 g, 46%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.4, 3H), 1.34-1.80 (m, 4H), 2.29(s, 3H), 2.64-2.74 (m, 2H), 3.89 (s, 2H), 6.41 (d, J=1.1, 1H), 7.13-7.86(m, 10H), 8.18 (s, 1H)

6-Butyl-3-(3-furyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(3-furyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(3-furyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(3-furyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(3-furyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(3-furyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 2076-butyl-3-(4-fluoro-3-methylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

207a)4′-{[4-butyl-1-(4-fluoro-3-methylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-fluoro-3-methylphenyl)boronic acid (1.0 g), triethylamine(2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) inmethylene chloride (15 mL) was added copper(II) acetate (1.0 g), and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate, the insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowviscous substance (1.11 g, 85%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.2, 3H), 1.33-1.73 (m, 4H), 2.17(s, 3H), 2.32 (d, J=1.9, 3H), 2.55-2.78 (m, 2H), 3.96 (s, 2H), 6.97-7.79(m, 11H)

207b)6-butyl-3-(4-fluoro-3-methylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.5 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-fluoro-3-methylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.11 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.58g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.53 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.85 g, 68%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.2, 3H), 1.34-1.76 (m, 4H), 2.12(s, 3H), 2.26 (s, 3H), 2.59-2.76 (m, 2H), 3.86 (s, 2H), 6.83-7.80 (m,11H), 8.65 (s, 1H)

Example 2086-butyl-3-(4-methoxy-3-methylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

208a)4′-{[4-butyl-1-(4-methoxy-3-methylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-methoxy-3-methylphenyl)boronic acid (1.0 g), triethylamine(2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) inmethylene chloride (15 mL) was added copper(II) acetate (1.0 g), and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate. The insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowviscous substance (1.31 g, 98%).

¹H NMR (300 MHz, CDCl₃) δ 0.91-0.97 (m, 3H), 1.32-1.74 (m, 4H), 2.18 (s,3H), 2.24 (s, 3H), 2.59-2.72 (m, 2H), 3.86 (s, 3H), 3.96 (s, 2H),6.85-7.80 (m, 11H)

208b)6-butyl-3-(4-methoxy-3-methylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.5 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-methoxy-3-methylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.31 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.67g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.61 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.96 g, 65%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.2, 3H), 1.31-1.79 (m, 4H), 2.12(s, 3H), 2.18 (s, 3H), 2.56-2.74 (m, 2H), 3.85 (s, 3H), 3.86 (br s.,2H), 6.79-7.78 (m, 11H), 8.66 (s, 1H)

Example 2096-butyl-3-(3,4-dimethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

209a)4′-{[4-butyl-1-(3,4-dimethoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (3,4-dimethoxyphenyl)boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylenechloride (15 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred for 2 days. The reaction mixture was diluted with ethylacetate. The insoluble material was filtered off through celite, and thefiltrate was concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.28 g, 92%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.4, 3H), 1.34-1.70 (m, 4H), 2.20(s, 3H), 2.59-2.73 (m, 2H), 3.88 (s, 3H), 3.92 (s, 3H), 3.97 (s, 2H),6.69-7.78 (m, 11H)

209b)6-butyl-3-(3,4-dimethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.5 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3,4-dimethoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.28 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.63g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.58 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.84 g, 59%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.4, 3H), 1.37-1.75 (m, 4H), 2.14(s, 3H), 2.60-2.73 (m, 2H), 3.78 (s, 3H), 3.87 (s, 2H), 3.90 (s, 3H),6.50-7.76 (m, 11H), 8.80 (s, 1H)

Example 2106-butyl-3-(3-ethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

21a)4′-{[1-(3-bromophenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 3-bromophenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.00 g, 70%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.2, 3H), 1.31-1.71 (m, 4H), 2.18(s, 3H), 2.59-2.74 (m, 2H), 3.96 (s, 2H), 7.08-7.87 (m, 12H)

21b)4′-{[4-butyl-2-methyl-6-oxo-1-(3-vinylphenyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A suspension of4′-{[1-(3-bromophenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), vinyltributyltin (0.86 mL),dichlorobis(triphenylphosphine)palladium(II) and lithium chloride (0.25g) in N,N-dimethylformamide (10 mL) was stirred at 90° C. for 3 hr underan argon atmosphere. The mixture was allowed to cool to roomtemperature, 20% aqueous potassium fluoride solution was added, and themixture was stirred for 12 hr. The reaction mixture was diluted withethyl acetate, and the insoluble material was filtered off throughcelite. The filtrate was washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound as a pale-yellowviscous substance (0.45 g, 50%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.4, 3H), 1.34-1.72 (m, 4H), 2.18(s, 3H), 2.58-2.76 (m, 2H), 3.97 (s, 2H), 5.33 (d, J=11.0, 1H), 5.78 (d,J=17.4, 1H), 6.72 (dd, J=17.4, 11.0, 1H), 7.06-7.17 (m, 1H), 7.34-7.84(m, 11H)

210c)6-butyl-3-(3-ethylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of4′-{[4-butyl-2-methyl-6-oxo-1-(3-vinylphenyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.25 g) in ethanol (4 mL) was added 10% palladium-carbon (50% wet,0.015 g), and the mixture was stirred for 8 hr under hydrogenatmosphere. The reaction mixture was diluted with ethyl acetate. Theinsoluble material was filtered off through celite, and the solvent wasevaporated under reduced pressure. The residue was added to a mixture ofhydroxylammonium chloride (0.57 g), sodium hydrogen carbonate (0.92 g)and dimethyl sulfoxide (5 mL) stirred at 40° C. for 30 min, and themixture was stirred at 90° C. for 18 hr. The reaction mixture wasallowed to cool to room temperature, ethyl acetate and water were added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was evaporated. The residue was dissolved intetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.10 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.096 mL) were added, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.14 g, 48%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.4, 3H), 1.22 (t, J=7.6, 3H),1.37-1.76 (m, 4H), 2.11 (s, 3H), 2.58-2.75 (m, 4H), 3.88 (s, 2H),6.87-7.79 (m, 12H), 8.58 (s, 1H)

Example 211

6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(3-vinylphenyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.44 g), sodium hydrogencarbonate (0.71 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-6-oxo-1-(3-vinylphenyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.19 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.06g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.056 mL) were added,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.088 g, 40%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.2, 3H), 1.33-1.76 (m, 4H), 2.11(s, 3H), 2.58-2.77 (m, 2H), 3.86 (s, 2H), 5.32 (d, J=11.0, 1H), 5.76 (d,J=17.4, 1H), 6.67 (dd, J=17.4, 11.0, 1H), 6.95-7.76 (m, 12H), 8.87 (s,1H)

Example 2126-butyl-3-[3-(2-methoxyethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

212a)4′-({4-butyl-1-[3-(2-methoxyethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[4-butyl-1-(3-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.69 g) and 1-bromo-2-methoxyethane (0.43 mL) in N,N-dimethylformamide(7 mL) was added cesium carbonate (0.99 g), and the mixture was stirredat 70° C. for 5 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.69 g, 90%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.2, 3H), 1.33-1.70 (m, 4H), 2.18(s, 3H), 2.61-2.71 (m, 2H), 3.44 (s, 3H), 3.75 (t, J=4.5, 2H), 3.97 (s,2H), 4.03-4.23 (m, 2H), 6.74-7.79 (m, 12H)

212b)6-butyl-3-[3-(2-methoxyethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.95 g), sodium hydrogencarbonate (1.40 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[3-(2-methoxyethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.69 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.33g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.34 g, 44%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.4, 3H), 1.34-1.78 (m, 4H), 2.15(s, 3H), 2.62-2.77 (m, 2H), 3.43 (s, 3H), 3.73 (t, J=4.7, 2H), 3.88 (s,2H), 4.00-4.18 (m, 2H), 6.65-7.83 (m, 12H), 8.51 (s, 1H)

Example 2132-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenyl-6-propylpyrimidin-4(3H)-one

213a)4′-[(2-methyl-6-oxo-1-phenyl-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), phenylboronic acid (1.00 g), triethylamine (1.95 mL), pyridine(1.13 mL) and molecular sieves 4 A (1.0 g) in methylene chloride (15 mL)was added copper(II) acetate (1.02 g), and the mixture was stirred for 2days. The reaction mixture was diluted with ethyl acetate. The insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.83 g, 68%).

¹H NMR (300 MHz, CDCl₃) δ 0.98-1.04 (m, 3H), 1.58-1.80 (m, 2H), 2.16 (s,3H), 2.56-2.73 (m, 2H), 3.98 (s, 2H), 7.16-7.79 (m, 13H)

213b)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.40 g), sodium hydrogencarbonate (2.00 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(2-methyl-6-oxo-1-phenyl-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.83 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.48g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.44 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.57 g, 41%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.4, 3H), 1.55-1.87 (m, 2H), 2.09(s, 3H), 2.51-2.73 (m, 2H), 3.86 (s, 2H), 6.87-7.82 (m, 13H), 8.97 (s,1H)

Example 2146-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methylpyrimidin-4(3H)-one

214a)4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(1.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (1.0 g),triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g),and the mixture was stirred for 2 days. The reaction mixture was dilutedwith ethyl acetate. The insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (1.40 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.4, 3H), 1.31-1.72 (m, 4H), 2.20(s, 3H), 2.48-2.81 (m, 2H), 3.08-3.47 (m, 2H), 3.98 (s, 2H), 4.64 (t,J=9.1, 2H), 6.68-7.96 (m, 10H)

214b)6-butyl-3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.85 g), sodium hydrogencarbonate (2.68 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(1.40 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.56g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.89 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.2, 3H), 1.22-1.60 (m, 4H), 2.09(s, 3H), 2.44-2.55 (m, 2H), 3.22 (t, J=8.7, 2H), 3.84 (s, 2H), 4.60 (t,J=8.5, 2H), 6.81-7.76 (m, 10H), 12.46 (s, 1H)

Example 2156-butyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-(3-methylphenyl)pyrimidin-4(3H)-one

215a)4′-{[4-butyl-2-methyl-1-(3-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(1.0 g), (3-methylphenyl)boronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.35 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.4, 3H), 1.30-1.73 (m, 4H), 2.17(s, 3H), 2.40 (s, 3H), 2.53-2.77 (m, 2H), 3.98 (s, 2H), 6.54-8.02 (m,11H)

215b)6-butyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-(3-methylphenyl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.85 g), sodium hydrogencarbonate (2.68 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(3-methylphenyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(1.35 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.56g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.94 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.88 (m, 3H), 1.22-1.60 (m, 4H), 2.07(s, 3H), 2.36 (s, 3H), 2.48-2.58 (m, 2H), 3.86 (s, 2H), 6.95-7.75 (m,11H), 12.46 (s, 1H)

Example 2166-butyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[3-(1-hydroxyethyl)phenyl]-2-methylpyrimidin-4(3H)-one

216a)4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(2.0 g), (3-acetylphenyl)boronic acid (2.0 g), triethylamine (4.0 mL),pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride(40 mL) was added copper(II) acetate (2.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.99 g, 76%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.4, 3H), 1.32-1.72 (m, 4H), 2.17(s, 3H), 2.63 (s, 3H), 2.65-2.73 (m, 2H), 3.99 (s, 2H), 7.12-8.13 (m,11H)

216b)4′-({4-butyl-1-[3-(1-hydroxyethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile

To a solution of4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(1.17 g) in ethanol (10 mL) was added sodium tetrahydroboron (0.11 g),and the mixture was stirred for 3 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was evaporated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.97 g, 82%).

¹H NMR (300 MHz, CDCl₃) δ 0.91-0.97 (m, 3H), 1.34-1.70 (m, 7H),2.09-2.27 (m, 4H), 2.58-2.71 (m, 2H), 3.98 (s, 2H), 4.86-5.01 (m, 1H),7.05-7.81 (m, 11H)

216c)6-butyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[3-(1-hydroxyethyl)phenyl]-2-methylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.36 g), sodium hydrogencarbonate (1.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[3-(1-hydroxyethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)-3′-fluorobiphenyl-2-carbonitrile(0.97 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.35g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.89 g, 60%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.3, 3H), 1.31-1.80 (m, 8H), 2.13(d, J=10.0, 3H), 2.42-2.92 (m, 2H), 3.85 (s, 2H), 4.72-4.91 (m, 1H),6.75-7.73 (m, 12H)

Example 2176-butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

217a)4′-({4-butyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(3-acetylphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) in tetrahydrofuran (10 mL) was added methylmagnesium bromide(1.0 M tetrahydrofuran solution, 2.5 mL) at −78° C. under an argonatmosphere, and the mixture was stirred for 12 hr while allowing to warmto room temperature. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate, and the solvent was evaporated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (0.54 g, 52%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.4, 3H), 1.33-1.75 (m, 10H),2.07-2.21 (m, 4H), 2.56-2.77 (m, 2H), 3.88-4.06 (m, 2H), 7.05-7.78 (m,12H)

217b)6-butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.6 g), sodium hydrogencarbonate (0.92 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({4-butyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.19g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.33 g, 54%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.3, 3H), 1.36-1.82 (m, 10H), 2.13(s, 3H), 2.58-2.84 (m, 2H), 3.29 (s, 1H), 3.74-3.96 (m, 2H), 6.87-7.77(m, 12H), 9.48 (s, 1H)

6-Butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 218

2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-pentyl-3-phenylpyrimidin-4(3H)-one

To a suspension of4′-[(2-methyl-6-oxo-4-pentyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), phenylboronic acid (1.00 g), triethylamine (2.0 mL), pyridine(1.0 mL) and molecular sieves 4 A (2.0 g) in methylene chloride (15 mL)was added copper(II) acetate (1.0 g), and the mixture was stirred for 2days. The reaction mixture was diluted with ethyl acetate. The insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was added to a mixture of hydroxylammoniumchloride (1.87 g), sodium hydrogen carbonate (2.71 g) and dimethylsulfoxide (14 mL) previously stirred at 40° C. for 30 min, and themixture was stirred at 90° C. for 18 hr. The reaction mixture wasallowed to cool to room temperature, ethyl acetate and water were added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was evaporated. The residue was dissolved intetrahydrofuran (15 mL), N,N′-carbonyldiimidazole (0.57 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.52 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.67 g, 49%).

¹H NMR (300 MHz, CDCl₃) δ 0.88-0.95 (m, 3H), 1.31-1.84 (m, 6H), 2.11 (s,3H), 2.56-2.76 (m, 2H), 3.87 (s, 2H), 7.04-7.83 (m, 13H), 8.77 (s, 1H)

Example 2196-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-pyridin-3-ylpyrimidin-4(3H)-one

219a)4′-[(4-butyl-2-methyl-6-oxo-1-pyridin-3-yl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), pyridin-3-ylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate,the insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.45 g, 37%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.4, 3H), 1.34-1.73 (m, 4H), 2.17(s, 3H), 2.51-2.80 (m, 2H), 3.88-4.03 (m, 2H), 7.33-7.80 (m, 10H), 8.54(d, J=2.3, 1H), 8.73 (dd, J=4.9, 1.5, 1H)

219b)6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-pyridin-3-ylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.70 g), sodium hydrogencarbonate (1.0 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-[(4-butyl-2-methyl-6-oxo-1-pyridin-3-yl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.45 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.22g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.17 g, 34%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.2, 3H), 1.31-1.81 (m, 4H), 2.13(s, 3H), 2.58-2.80 (m, 2H), 3.89 (s, 2H), 7.08-7.86 (m, 11H), 8.32-8.46(m, 1H), 8.54-8.72 (m, 1H)

Example 2203-(2,3-dihydro-1-benzofuran-5-yl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

220a)4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a suspension of3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(5.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (5.0 g),triethylamine (10.0 mL), pyridine (5.0 mL) and molecular sieves 4 A(10.0 g) in methylene chloride (100 mL) was added copper(II) acetate(5.0 g), and the mixture was stirred for 2 days. The reaction mixturewas diluted with ethyl acetate. The insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (5.41 g, 82%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.4, 3H), 1.55-1.80 (m, 2H), 2.20(s, 3H), 2.56-2.72 (m, 2H), 3.14-3.35 (m, 2H), 3.98 (s, 2H), 4.64 (t,J=9.1, 2H), 6.74-7.85 (m, 10H)

220b)3-(2,3-dihydro-1-benzofuran-5-yl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (7.80 g), sodium hydrogencarbonate (11.4 g) and dimethyl sulfoxide (55 mL) was stirred at 40° C.for 30 min,4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(5.41 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the aqueous layer was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate, and the solvent was evaporated. Theresidue was dissolved in tetrahydrofuran (55 mL),N,N′-carbonyldiimidazole (2.74 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (2.57 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (2.94 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.45-1.66 (m, 2H), 2.09(s, 3H), 2.39-2.50 (m, 2H), 3.22 (t, J=8.7, 2H), 3.85 (s, 2H), 4.60 (t,J=8.9, 2H), 6.81-7.75 (m, 10H), 12.45 (s, 1H)

Example 2216-butyl-3-(3-cyclopropylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

221a)4′-{[4-butyl-1-(3-cyclopropylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A suspension of4′-{[1-(3-bromophenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), cyclopropylboronic acid (0.34 g), palladium acetate (0.04 g),tricyclohexylphosphine (0.11 g) and potassium phosphate (1.45 g) intoluene-water (95:5, 10 mL) was stirred at 100° C. for 12 hr under anargon atmosphere. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas washed with saturated brine and dried over anhydrous magnesiumsulfate, and the solvent was evaporated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (0.95 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.61-0.83 (m, 2H), 0.96-1.06 (m, 2H), 1.26 (t,J=7.2, 3H), 1.35-1.50 (m, 2H), 1.56-1.69 (m, 2H), 1.86-1.99 (m, 1H),2.16 (s, 3H), 2.59-2.73 (m, 2H), 3.97 (s, 2H), 6.83-7.83 (m, 12H)

221b)6-butyl-3-(3-cyclopropylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.10 g), sodium hydrogencarbonate (1.64 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-cyclopropylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.95 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.45g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.44 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.49 g, 47%).

¹H NMR (300 MHz, CDCl₃) δ 0.45-1.04 (m, 7H), 1.31-1.77 (m, 4H),1.79-1.98 (m, 1H), 2.12 (s, 3H), 2.55-2.77 (m, 2H), 3.88 (s, 2H),6.76-7.81 (m, 12H), 8.72 (s, 1H)

Example 2226-butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

222a)4′-{[4-butyl-1-(4-ethoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-ethoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.25 g, 93%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.3, 3H), 1.35-1.49 (m, 5H),1.55-1.71 (m, 2H), 2.17 (s, 3H), 2.62-2.70 (m, 2H), 3.96 (s, 2H), 4.07(q, J=7.0, 2H), 6.96-7.16 (m, 4H), 7.36-7.79 (m, 8H)

222b)6-butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.82 g), sodium hydrogencarbonate (2.64 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-ethoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.25 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (13 mL), N,N′-carbonyldiimidazole (0.54g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (1.03 g, 73%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.36-1.73 (m, 7H), 2.10(s, 3H), 2.60-2.71 (m, 2H), 3.84 (s, 2H), 4.04 (q, J=7.0, 2H), 6.84-7.73(m, 12H), 9.10 (s, 1H)

6-Butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 2236-butyl-3-(3-fluorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

223a)4′-{[4-butyl-1-(3-fluorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (3-fluorophenyl)boronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylene chloride(15 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate.The insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.16 g, 92%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.32-1.72 (m, 4H), 2.18(s, 3H), 2.60-2.74 (m, 2H), 3.96 (s, 2H), 6.96-7.24 (m, 3H), 7.36-7.80(m, 9H)

223b)6-butyl-3-(3-fluorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.79 g), sodium hydrogencarbonate (2.60 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-fluorophenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.16 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (13 mL), N,N′-carbonyldiimidazole (0.54g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.87 g, 66%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.3, 3H), 1.36-1.74 (m, 4H), 2.11(s, 3H), 2.64-2.73 (m, 2H), 3.79-3.91 (m, 2H), 6.82-7.70 (m, 12H), 8.92(s, 1H)

Example 2243-(1,3-benzodioxol-5-yl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

224a)4′-{[1-(1,3-benzodioxol-5-yl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 1,3-benzodioxol-5-ylboronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylenechloride (15 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred at room temperature for 2 days. The reaction mixture wasdiluted with ethyl acetate. The insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (0.99 g, 74%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.2, 3H), 1.30-1.74 (m, 4H), 2.21(s, 3H), 2.53-2.76 (m, 2H), 3.96 (s, 2H), 5.87-6.19 (m, 2H), 6.55-7.02(m, 3H), 7.34-7.80 (m, 8H)

224b)3-(1,3-benzodioxol-5-yl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.45 g), sodium hydrogencarbonate (2.10 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(1,3-benzodioxol-5-yl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.99 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.49g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.46 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.86 g, 77%).

¹H NMR (300 MHz, CDCl₃) δ 0.92-1.01 (m, 3H), 1.36-1.76 (m, 4H), 2.18 (s,3H), 2.58-2.78 (m, 2H), 3.87 (s, 2H), 6.03 (dd, J=10.4, 1.3, 2H),6.47-7.87 (m, 11H), 8.57 (s, 1H)

Example 225N-{3-[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]phenyl}acetamide

225a)N-{3-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]phenyl}acetamide

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), [3-(acetylamino)phenyl]boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0 g) in methylenechloride (15 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred at room temperature for 2 days. The reaction mixture wasdiluted with ethyl acetate. The insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (0.38 g, 28%).

¹H NMR (300 MHz, CDCl₃) δ 0.72-1.08 (m, 3H), 1.34-1.71 (m, 4H), 1.84 (s,3H), 2.19 (s, 3H), 2.58-2.75 (m, 2H), 3.91-4.09 (m, 2H), 6.71-7.81 (m,12H), 8.66 (s, 1H)

225b)N-{3-[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]phenyl}acetamide

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.78 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,N-{3-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]phenyl}acetamide(0.38 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (4 mL), N,N′-carbonyldiimidazole (0.20g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.26 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80-0.89 (m, 3H), 1.22-1.58 (m, 4H), 2.06(s, 3H), 2.07 (s, 3H), 2.50-2.58 (m, 2H), 3.87 (s, 2H), 6.96-7.74 (m,12H), 10.16 (s, 1H), 12.40 (s, 1H)

Example 2266-butyl-2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

226a)4′-{[4-butyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.0 g),triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (1.0g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was diluted with ethyl acetate. The insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (1.42 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.2, 3H), 1.31-1.82 (m, 7H), 2.20(d, J=4.9, 3H), 2.59-2.70 (m, 2H), 2.78-2.95 (m, 1H), 3.26-3.44 (m, 1H),3.96 (s, 2H), 4.88-5.09 (m, 1H), 6.75-7.79 (m, 11H)

226b)6-butyl-2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.95 g), sodium hydrogencarbonate (2.82 g) and dimethyl sulfoxide (14 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.42 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (14 mL), N,N′-carbonyldiimidazole (0.68g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.63 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (1.11 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.74-0.94 (m, 3H), 1.21-1.57 (m, 7H), 2.08(d, J=3.4, 3H), 2.48-2.56 (m, 2H), 2.74-2.93 (m, 1H), 3.31-3.44 (m, 1H),3.85 (s, 2H), 4.89-5.10 (m, 1H), 6.73-7.79 (m, 11H), 12.40 (s, 1H)

Example 2276-butyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)pyrimidin-4(3H)-one

227a)4′-{[4-butyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.5 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (1.0 g),triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (2.0g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was diluted with ethyl acetate. The insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.63 g, 93%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.2, 3H), 1.31-1.74 (m, 7H), 2.20(d, J=4.5, 3H), 2.56-2.72 (m, 2H), 2.74-3.01 (m, 1H), 3.14-3.58 (m, 1H),3.97 (s, 2H), 4.50-5.42 (m, 1H), 6.55-7.89 (m, 10H)

227b)6-butyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.86 g), sodium hydrogencarbonate (1.25 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.63 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (14 mL), N,N′-carbonyldiimidazole (0.30g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.42 g, 59%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.4, 3H), 1.22-1.58 (m, 7H), 2.09(d, J=3.4, 3H), 2.44-2.54 (m, 2H), 2.73-2.89 (m, 1H), 3.28-3.42 (m, 1H),3.84 (s, 2H), 4.76-5.14 (m, 1H), 6.67-7.87 (m, 10H), 12.47 (s, 1H)

Example 228

6-butyl-3-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g), (1-oxo-2,3-dihydro-1H-inden-5-yl)boronic acid (2.87 g),triethylamine (6.0 mL), pyridine (3.0 mL) and molecular sieves 4 A (6.0g) in tetrahydrofuran (50 mL) was added copper(II) acetate (3.0 g), andthe mixture was stirred for 2 days. The reaction mixture was dilutedwith ethyl acetate and the insoluble material was filtered off throughcelite. The filtrate was concentrated and the residue was crudelypurified by silica gel column chromatography. To a solution of thecrudely purified product in ethanol (8 mL) was added sodiumtetrahydroboron (0.083 g), and the mixture was stirred for 3 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was added to a mixture ofhydroxylammonium chloride (0.83 g), sodium hydrogen carbonate (1.2 g)and dimethyl sulfoxide (6 mL) previously stirred at 40° C. for 30 min,and the mixture was stirred at 90° C. for 18 hr. The reaction mixturewas allowed to cool to room temperature, ethyl acetate and water wereadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate, and the solvent was evaporated. The residue was dissolved intetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.21 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.12 g, 18%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.2, 3H), 1.21-1.59 (m, 4H),1.73-1.93 (m, 1H), 2.06 (d, J=6.1, 3H), 2.29-3.06 (m, 5H), 3.86 (s, 2H),5.10 (q, J=6.1, 1H), 5.38 (dd, J=5.9, 4.0, 1H), 7.08-7.78 (m, 11H),12.39 (s, 1H)

Example 229

6-butyl-2-methyl-3-(1-oxo-2,3-dihydro-1H-inden-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of6-butyl-3-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.055 g) in acetonitrile (2 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.085 g),and the mixture was stirred for 2 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.027 g,49%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.2, 3H), 1.35-1.78 (m, 4H), 2.15(s, 3H), 2.63-2.83 (m, 4H), 3.12-3.24 (m, 2H), 3.91 (s, 2H), 7.10-7.93(m, 11H)

Example 2306-butyl-3-(4-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

230a)4′-{[4-butyl-1-(4-methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g), (4-methoxyphenyl)boronic acid (3.0 g), triethylamine (6.0 mL),pyridine (3.0 mL) and molecular sieves 4 A (6.0 g) in methylene chloride(50 mL) was added copper(II) acetate (3.0 g), and the mixture wasstirred at room temperature for 2 days. The reaction mixture was dilutedwith ethyl acetate. The insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (3.03 g, 78%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.4, 3H), 1.31-1.85 (m, 4H), 2.18(s, 3H), 2.51-2.83 (m, 2H), 3.85 (s, 3H), 3.96 (s, 2H), 6.83-7.82 (m,12H)

230b)6-butyl-3-(4-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.50 g), sodium hydrogencarbonate (2.18 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(4-methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.46g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.88 g, 78%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.2, 3H), 1.28-1.77 (m, 4H), 2.10(s, 3H), 2.40-2.77 (m, 2H), 3.83 (s, 2H), 3.86 (s, 3H), 6.85-7.83 (m,12H), 8.48 (s, 1H)

Example 231

6-butyl-3-(2,3-dihydro-1-benzofuran-6-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 2,3-dihydro-1-benzofuran-6-ylboronic acid (1.0 g),triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (2.0g) in methylene chloride (15 mL) was added copper(II) acetate (1.0 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was diluted with ethyl acetate. The insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was crudely purified by silica gel column chromatography. Thecrudely purified product was added to a mixture of hydroxylammoniumchloride (1.95 g), sodium hydrogen carbonate (2.82 g) and dimethylsulfoxide (14 mL) previously stirred at 40° C. for 30 min, and themixture was stirred at 90° C. for 18 hr. The reaction mixture wasallowed to cool to room temperature, ethyl acetate and water were added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate,and the solvent was evaporated. The residue was dissolved intetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.59 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.54 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (1.24 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.4, 3H), 1.20-1.53 (m, 4H), 2.09(s, 3H), 2.46-2.57 (m, 2H), 3.24 (t, J=8.8, 2H), 3.86 (s, 2H), 4.61 (t,J=8.8, 2H), 6.70-7.74 (m, 11H), 12.41 (s, 1H)

Example 232

6-butyl-3-(4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-isopropoxyphenyl)boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (2.0 g) intetrahydrofuran (15 mL) was added copper(II) acetate (1.0 g), and themixture was stirred at room temperature for 2 days. The reaction mixturewas diluted with ethyl acetate. The insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue wasroughly purified by silica gel column chromatography. The crudelypurified product was added to a mixture of hydroxylammonium chloride(1.95 g), sodium hydrogen carbonate (2.82 g) and dimethyl sulfoxide (14mL) previously stirred at 40° C. for 30 min, and the mixture was stirredat 90° C. for 18 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate, and thesolvent was evaporated. The residue was dissolved in tetrahydrofuran (10mL), N,N′-carbonyldiimidazole (0.59 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.54 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (1.16 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.4, 3H), 1.15-1.67 (m, 10H),2.06 (s, 3H), 2.50-2.56 (m, 2H), 3.86 (s, 2H), 4.58-4.78 (m, 1H),6.94-7.75 (m, 12H), 12.41 (s, 1H)

Example 2336-butyl-3-(3-fluoro-4-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

233a)4′-{[4-butyl-1-(3-fluoro-4-methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g), (3-fluoro-4-methoxyphenyl)boronic acid (3.0 g), triethylamine(6.0 mL), pyridine (3.0 mL) and molecular sieves 4 A (6.0 g) inmethylene chloride (50 mL) was added copper(II) acetate (3.0 g), and themixture was stirred at room temperature for 2 days. The reaction mixturewas diluted with ethyl acetate. The insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (2.62 g, 65%).

¹H NMR (300 MHz, CDCl₃) δ 0.72-1.04 (m, 3H), 1.28-1.78 (m, 4H), 2.19 (s,3H), 2.48-2.76 (m, 2H), 3.94 (s, 3H), 3.96 (s, 2H), 6.91-7.82 (m, 11H)

233b)6-butyl-3-(3-fluoro-4-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.46 g), sodium hydrogencarbonate (2.10 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-fluoro-4-methoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.44g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.40 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.78 g, 69%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.4, 3H), 1.19-1.64 (m, 4H), 2.08(s, 3H), 2.41-2.58 (m, 2H), 3.86 (s, 2H), 3.90 (s, 3H), 7.14-7.75 (m,11H), 12.41 (s, 1H)

Example 2346-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

234a)4′-{[4-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.43g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A(2.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.0g), and the mixture was stirred at room temperature for 2 days. Thereaction mixture was diluted with ethyl acetate. The insoluble materialwas filtered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.68 g, 60%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (t, J=7.4, 3H), 1.35-1.46 (m, 2H), 1.48(s, 3H), 1.52 (s, 3H), 1.55-1.71 (m, 2H), 2.20 (s, 3H), 2.61-2.71 (m,2H), 3.06 (s, 2H), 3.96 (s, 2H), 6.76-7.03 (m, 3H), 7.33-7.83 (m, 8H)

234b)6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.1 g), sodium hydrogencarbonate (1.69 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.68 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (7 mL), N,N′-carbonyldiimidazole (0.33g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.46 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.2, 3H), 1.14-1.63 (m, 10H),2.08 (s, 3H), 2.49-2.61 (m, 2H), 3.05 (s, 2H), 3.85 (s, 2H), 6.68-7.79(m, 11H), 12.40 (s, 1H)

6-Butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 2352-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

235a)4′-{[2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (2-methyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.5 g),triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (2.0g) in tetrahydrofuran (15 mL) was added copper(II) acetate (1.0 g), andthe mixture was stirred at room temperature for 2 days. The reactionmixture was diluted with ethyl acetate. The insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.68 g, 49%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.43-1.78 (m, 5H), 2.20(d, J=4.9, 3H), 2.58-2.70 (m, 2H), 2.79-2.94 (m, 1H), 3.25-3.43 (m, 1H),3.97 (s, 2H), 4.89-5.10 (m, 1H), 6.79-7.79 (m, 11H)

235b)2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.20 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-1-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate, and the solvent was evaporated. The residuewas dissolved in tetrahydrofuran (7 mL), N,N′-carbonyldiimidazole (0.35g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.37 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.2, 3H), 1.36-1.64 (m, 5H), 2.08(d, J=3.0, 3H), 2.45-2.55 (m, 2H), 2.74-2.90 (m, 1H), 3.30-3.42 (m, 1H),3.86 (s, 2H), 4.89-5.09 (m, 1H), 6.76-7.73 (m, 11H), 12.39 (s, 1H)

2-Methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   2-methyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 236 methyl5-[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]-2,3-dihydro-1-benzofuran-7-carboxylate

236a) methyl5-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]-2,3-dihydro-1-benzofuran-7-carboxylate

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.0 g), [7-(methoxycarbonyl)-2,3-dihydro-1-benzofuran-5-yl]boronic acid(1.64 g), triethylamine (4.0 mL), pyridine (2.0 mL) and molecular sieves4 A (4.0 g) in methylene chloride (30 mL) was added copper(II) acetate(2.0 g), and the mixture was stirred at room temperature for 2 days. Thereaction mixture was diluted with ethyl acetate, the insoluble materialwas filtered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.24 g, 8%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.4, 3H), 1.30-1.71 (m, 4H), 2.21(s, 3H), 2.54-2.77 (m, 2H), 3.11-3.45 (m, 2H), 3.89 (s, 3H), 3.91-4.02(m, 2H), 4.81 (t, J=8.9, 2H), 7.15-7.79 (m, 10H)

236b) methyl5-[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]-2,3-dihydro-1-benzofuran-7-carboxylate

A mixture of hydroxylammonium chloride (0.31 g), sodium hydrogencarbonate (0.44 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min, methyl5-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]-2,3-dihydro-1-benzofuran-7-carboxylate(0.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (2.6 mL). N,N′-carbonyldiimidazole(0.055 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.051 mL) wereadded, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.081 g,31%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.2, 3H), 1.22-1.58 (m, 4H), 2.09(s, 3H), 2.48-2.57 (m, 2H), 3.27 (t, J=8.9, 2H), 3.80 (s, 3H), 3.86 (s,2H), 4.73 (t, J=8.7, 2H), 7.13-7.73 (m, 10H), 12.41 (s, 1H)

Example 2376-butyl-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

237a)4′-{[4-butyl-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g),(3-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)boronicacid (3.07 g), triethylamine (6.0 mL), pyridine (3.0 mL) and molecularsieves 4 A (6.0 g) in methylene chloride (50 mL) was added copper(II)acetate (3.0 g), and the mixture was stirred at room temperature for 2days. The reaction mixture was diluted with ethyl acetate, the insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (3.7 g, 73%).

¹H NMR (300 MHz, CDCl₃) δ 0.14 (s, 6H), 0.90-0.99 (m, 12H), 1.38-1.71(m, 4H), 1.89-2.03 (m, 1H), 2.18 (s, 3H), 2.37-3.19 (m, 5H), 3.98 (s,2H), 5.28 (t, J=6.8, 1H), 6.95-8.24 (m, 11H)

237b)6-butyl-3-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.50 g), sodium hydrogencarbonate (3.70 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. Themixture was allowed to cool to room temperature, ethyl acetate and waterwere added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wasdissolved in tetrahydrofuran (10.0 mL). N,N′-carbonyldiimidazole (0.36g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.02 g, 42%).

¹H NMR (300 MHz, CDCl₃) δ 0.14 (s, 6H), 0.91 (s, 9H), 0.97 (t, J=7.2,3H), 1.38-1.76 (m, 4H), 1.89-2.03 (m, 1H), 2.16 (s, 3H), 2.31-3.17 (m,5H), 3.93 (s, 2H), 5.25 (t, J=6.8, 1H), 6.95-7.89 (m, 12H)

237c)6-butyl-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of6-butyl-3-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(1.02 g) in tetrahydrofuran (8 mL) was added tetrabutylammonium fluoride(0.60 g), and the mixture was stirred at 50° C. for 12 hr. The reactionmixture was allowed to cool to room temperature, ethyl acetate and waterwere added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.49 g, 59%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.2, 3H), 1.22-1.57 (m, 4H),1.74-1.93 (m, 1H), 2.06 (d, J=3.8, 3H), 2.29-2.57 (m, 3H), 2.67-3.08 (m,2H), 3.87 (s, 2H), 5.09 (q, J=6.8, 1H), 5.34 (dd, J=8.5, 5.9, 1H),7.04-7.80 (m, 11H), 12.40 (s, 1H)

Example 238

6-butyl-2-methyl-3-(3-oxo-2,3-dihydro-1H-inden-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of6-butyl-3-(3-hydroxy-2,3-dihydro-1H-inden-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.30 g) in acetonitrile (3 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.35 g),and the mixture was stirred at room temperature for 3 hr. Ethyl acetate,water and sodium thiosulfate were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.25 g,82%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.4, 3H), 1.22-1.58 (m, 4H), 2.06(s, 3H), 2.47-2.57 (m, 2H), 2.66-2.80 (m, 2H), 3.11-3.25 (m, 2H), 3.87(s, 2H), 7.07-7.80 (m, 11H), 12.40 (s, 1H)

Example 2393-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

239a)4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(4.0 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (4.0g), triethylamine (8.0 mL), pyridine (4.0 mL) and molecular sieves 4 A(8.0 g) in methylene chloride (60 mL) was added copper(II) acetate (4.0g), and the mixture was stirred at room temperature for 2 days. Thereaction mixture was diluted with ethyl acetate, the insoluble materialwas filtered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow solid (4.28 g, 75%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.48 (s, 3H), 1.52 (s,3H), 1.61-1.77 (m, 2H), 2.20 (s, 3H), 2.60-2.70 (m, 2H), 3.06 (s, 2H),3.97 (s, 2H), 6.75-7.81 (m, 11H)

239b)3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (6.1 g), sodium hydrogencarbonate (8.80 g) and dimethyl sulfoxide (50 mL) was stirred at 40° C.for 30 min,4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(4.28 g) was added, and the mixture was stirred at 90° C. for 23 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (50 mL). N,N′-carbonyldiimidazole (1.7g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (1.57 mL) were added, andthe mixture was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (3.64 g, 76%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4, 3H), 1.44 (s, 3H), 1.45 (s,3H), 1.48-1.61 (m, 2H), 2.08 (s, 3H), 2.45-2.54 (m, 2H), 3.05 (s, 2H),3.85 (s, 2H), 6.74-7.74 (m, 11H), 12.40 (s, 1H)

239c) Crystalline3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

(1) A solution of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(150 g) in acetone (400 ml) was stirred for 3 days. The precipitate wascollected and washed with acetone. The solid was dried under reducedpressure at 120° C. for 8 hr to give the title compound (136 g, 91%) ascolorless crystals.

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):4.76, 6.10, 7.30, 7.86, 8.16, 9.18, 9.60, 10.66, 11.28, 11.94, 12.58,13.34, 14.62, 15.10, 15.46, 16.34, 16.90, 17.76, 18.64, 19.34, 20.86,21.58, 22.42, 24.36, 24.86.

Anal calcd for C₃₃H₃₂N₄O₄: C, 72.24; H, 5.88; N, 10.21.

Found C, 71.97; H, 5.86; N, 10.14.

(2) To a solution of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(347 g) in methyl ethyl ketone (700 ml) was added heptane (1050 mL)dropwise at 60° C. and the mixture was allowed to cool to roomtemperature followed by stirring at this temperature for 12 hr. Theobtained precipitate was collected, washed with methyl ethyl ketone, anddried under reduced pressure at 80° C. for 5 hr to give the titlecompound (293 g, 90%) as colorless crystals.

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4, 3H), 1.44 (s, 3H), 1.45 (s,3H), 1.48-1.61 (m, 2H), 2.08 (s, 3H), 2.45-2.54 (m, 2H), 3.05 (s, 2H),3.85 (s, 2H), 6.74-7.74 (m, 11H), 12.40 (s, 1H)

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):4.38, 7.42, 8.90, 9.68, 10.92, 11.24, 11.90, 12.56, 12.88, 13.34, 14.06,14.92, 16.64, 17.30, 17.80, 18.70, 19.08, 19.40, 20.36, 20.90, 21.20,21.50, 21.98, 22.40, 22.72, 22.98, 23.68.

Anal calcd for C₃₃H₃₂N₄O₄: C, 72.24; H, 5.88; N, 10.21.

Found C, 72.11; H, 5.85; N, 10.26.

3-(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 2406-butyl-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

240a)4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a mixture of 2-methoxyethanimidamide hydrochloride (2.1 g) andmethanol (15 mL) were added sodium methoxide (28% methanol solution, 4.8g), and then a solution of ethyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (3.0 g) in methanol(25 mL) and 1,4-dioxane (10 mL) at 0° C., and the mixture was stirred atroom temperature for 16 hr. The reaction mixture was concentrated, andthe residue was adjusted to pH 5 with water (50 mL) and 50% aqueousacetic acid solution, and extracted with ethyl acetate. The obtainedethyl acetate layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (2.4 g,75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.19-1.34 (2H, m),1.37-1.50 (2H, m), 2.46-2.58 (5H, m), 3.33 (3H, s), 3.88 (2H, s), 4.23(2H, s), 7.33 (2H, d, J=8.3), 7.48 (2H, d, J=8.3), 7.51-7.62 (2H, m),7.72-7.82 (1H, m), 7.93 (1H, d, J=7.7), 12.37 (1H, br)

240b)6-butyl-2-(methoxymethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.89 g), sodium hydrogencarbonate (3.04 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-2-(methoxymethyl)-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.70 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.35 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.37 g,47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 1.19-1.37 (2H, m),1.37-1.63 (2H, m), 2.46-2.55 (5H, m), 3.84 (2H, s), 4.23 (2H, s),7.13-7.33 (4H, m), 7.46-7.61 (2H, m), 7.61-7.75 (2H, m), 12.36 (2H, s)

Example 2413-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

241a)4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (2.0 g),triethylamine (4.0 mL), pyridine (2.0 mL) and molecular sieves 4 A (4.0g) in methylene chloride (30 mL) was added copper(II) acetate (2.0 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was diluted with ethyl acetate, the insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (2.26 g, 84%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.55-1.79 (m, 2H), 2.20(d, J=2.3, 3H), 2.55-2.75 (m, 2H), 3.15-3.36 (m, 2H), 3.96 (s, 2H),4.50-4.71 (m, 2H), 6.54-7.80 (m, 11H)

241b)3-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (3.5 g), sodium hydrogencarbonate (5.0 g) and dimethyl sulfoxide (25 mL) was stirred at 40° C.for 30 min,4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.26 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (25 mL). N,N′-carbonyldiimidazole (0.97g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.61 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.2, 3H), 1.43-1.64 (m, 2H), 2.09(s, 3H), 2.45-2.54 (m, 2H), 3.15-3.29 (m, 2H), 3.86 (s, 2H), 4.61 (t,J=8.7, 2H), 6.73-7.76 (m, 11H), 12.39 (s, 1H)

Example 2423-(4-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

242a)4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.0 g), (4-methoxyphenyl)boronic acid (2.0 g), triethylamine (4.0 mL),pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride(30 mL) was added copper(II) acetate (2.0 g), and the mixture wasstirred at room temperature for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (2.15 g, 82%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.54-1.84 (m, 2H), 2.17(s, 3H), 2.54-2.78 (m, 2H), 3.85 (s, 3H), 3.97 (s, 2H), 6.89-7.86 (m,12H)

242b)3-(4-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (3.5 g), sodium hydrogencarbonate (5.0 g) and dimethyl sulfoxide (25 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.15 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (25 mL). N,N′-carbonyldiimidazole (0.97g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.46 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.42-1.64 (m, 2H), 2.06(s, 3H), 2.45-2.56 (m, 2H), 3.81 (s, 3H), 3.87 (s, 2H), 7.00-7.75 (m,12H), 12.39 (s, 1H)

Example 2433-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

243a)4′-{[1-(4-ethoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.0 g), (4-ethoxyphenyl)boronic acid (2.0 g), triethylamine (4.0 mL),pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride(30 mL) was added copper(II) acetate (2.0 g), and the mixture wasstirred at room temperature for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (2.47 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.43 (t, J=7.0, 3H),1.58-1.83 (m, 2H), 2.17 (s, 3H), 2.56-2.70 (m, 2H), 3.97 (s, 2H), 4.06(q, J=6.8, 2H), 6.93-7.79 (m, 12H)

243b)3-(4-ethoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (3.5 g), sodium hydrogencarbonate (5.0 g) and dimethyl sulfoxide (25 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-ethoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.47 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (25 mL). N,N′-carbonyldiimidazole (0.97g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.90 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (2.18 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.35 (t, J=7.0, 3H),1.44-1.63 (m, 2H), 2.06 (s, 3H), 2.45-2.55 (m, 2H), 3.86 (s, 2H), 4.08(q, J=7.0, 2H), 7.00-7.74 (m, 12H), 12.39 (br s, 1H)

Example 2443-(3-fluoro-4-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

244a)4′-{[1-(3-fluoro-4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (3-fluoro-4-methoxyphenyl)boronic acid (1.0 g), triethylamine(2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) intetrahydrofuran (10 mL) was added copper(II) acetate (1.0 g), and themixture was stirred at room temperature for 2 days. The reaction mixturewas diluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.24 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.58-1.77 (m, 2H), 2.19(s, 3H), 2.57-2.72 (m, 2H), 3.94 (s, 3H), 3.96 (s, 2H), 6.90-7.79 (m,11H)

244b)3-(3-fluoro-4-methoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.74 g), sodium hydrogencarbonate (2.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(3-fluoro-4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.45g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.04 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.45-1.62 (m, 2H), 2.09(s, 3H), 2.45-2.53 (m, 2H), 3.87 (s, 2H), 3.90 (s, 3H), 7.14-7.73 (m,11H), 12.39 (s, 1H)

Example 2453-(3-fluoro-4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

245a)4′-{[1-(3-fluoro-4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (3-fluoro-4-isopropoxyphenyl)boronic acid (1.0 g),triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was diluted with ethyl acetate, the insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (1.15 g, 80%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.2, 3H), 1.39 (t, J=6.6, 6H),1.60-1.79 (m, 2H), 2.19 (s, 3H), 2.59-2.70 (m, 2H), 3.96 (s, 2H),4.51-4.68 (m, 1H), 6.90-7.78 (m, 11H)

245b)3-(3-fluoro-4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogencarbonate (2.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(3-fluoro-4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.15 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.52g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.83 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.32 (dd, J=5.9, 2.5,6H), 1.45-1.62 (m, 2H), 2.09 (s, 3H), 2.46-2.54 (m, 2H), 3.87 (s, 2H),4.63-4.81 (m, 1H), 7.08-7.74 (m, 11H), 12.39 (s, 1H)

Example 2463-[4-(cyclopropylmethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

246a)4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(11.8 g) in methylene chloride (100 mL) was added boron tribromide (1.0M methylene chloride solution, 50 mL), and the mixture was stirred atroom temperature for 2 days. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow solid (12.22 g, 100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.97 (t, J=7.4, 3H), 1.51-1.69 (m, 2H), 2.27(s, 3H), 2.69 (t, J=7.8, 2H), 3.96 (s, 2H), 6.85-8.00 (m, 12H), 9.97 (s,1H)

246b)4′-({1-[4-(cyclopropylmethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and (bromomethyl)cyclopropane (0.70 mL) in N,N-dimethylformamide(10 mL) was added cesium carbonate (1.5 g), and the mixture was stirredat 70° C. for 12 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.93 g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 0.31-0.40 (m, 2H), 0.61-0.71 (m, 2H), 1.01 (t,J=7.2, 3H), 1.21-1.36 (m, 1H), 1.63-1.76 (m, 2H), 2.17 (s, 3H),2.60-2.70 (m, 2H), 3.83 (d, J=7.2, 2H), 3.96 (s, 2H), 6.96-7.77 (m, 12H)

246c)3-[4-(cyclopropylmethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(cyclopropylmethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.93 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.84 g, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.30-0.39 (m, 2H), 0.53-0.63 (m, 2H), 0.89(t, J=7.4, 3H), 1.19-1.32 (m, 1H), 1.45-1.62 (m, 2H), 2.06 (s, 3H),2.46-2.55 (m, 2H), 3.86 (s, 2H), 3.85-3.91 (m, 2H), 6.98-7.74 (m, 12H),12.39 (s, 1H)

Example 247

3-[4-(2,2-dimethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and 1-iodo-2,2-dimethylpropane (0.92 mL) inN,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), andthe mixture was stirred at 70° C. for 12 hr. The reaction mixture wasallowed to cool to room temperature, ethyl acetate and water were added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated and the residue was added to a mixture ofhydroxylammonium chloride (1.3 g), sodium hydrogen carbonate (1.9 g) anddimethyl sulfoxide (10 mL), which had been stirred at 40° C. for 30 min,and the mixture was stirred at 90° C. for 18 hr. The mixture was allowedto cool to room temperature, ethyl acetate and water were added to thereaction mixture, and the aqueous layer was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.37 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.78 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.02 (s, 9H), 1.45-1.63(m, 2H), 2.06 (s, 3H), 2.46-2.54 (m, 2H), 3.69 (s, 2H), 3.87 (s, 2H),6.99-7.79 (m, 12H), 12.38 (s, 1H)

Example 2483-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

248a)4′-({1-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and 2,2-dimethyloxirane (0.70 mL) in N,N-dimethylformamide (10mL) was added cesium carbonate (1.5 g), and the mixture was stirred at70° C. for 12 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.91 g, 78%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.2, 3H), 1.36 (s, 6H), 1.63-1.77(m, 2H), 2.18 (s, 3H), 2.20 (s, 1H), 2.62-2.68 (m, 2H), 3.83 (s, 2H),3.97 (s, 2H), 6.99-7.80 (m, 12H)

248b)3-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2-hydroxy-2-methylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.91 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.69 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.22 (s, 6H), 1.46-1.61(m, 2H), 2.06 (s, 3H), 2.46-2.54 (m, 2H), 3.77 (s, 2H), 3.86 (s, 2H),4.68 (s, 1H), 6.99-7.75 (m, 12H), 12.38 (s, 1H)

Example 2492-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-propoxyphenyl)-6-propylpyrimidin-4(3H)-one

249a)4′-{[2-methyl-6-oxo-1-(4-propoxyphenyl)-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and 1-iodopropane (1.1 mL) in N,N-dimethylformamide (10 mL) wasadded cesium carbonate (1.5 g), and the mixture was stirred at 80° C.for 5 hr. The reaction mixture was allowed to cool to room temperature,ethyl acetate and water were added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.91 g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.2, 3H), 1.26 (t, J=7.0, 3H),1.63-1.90 (m, 4H), 2.17 (s, 3H), 2.59-2.69 (m, 2H), 3.91-4.00 (m, 4H),6.94-7.77 (m, 12H)

249b)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-propoxyphenyl)-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.32 g), sodium hydrogencarbonate (1.92 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-6-oxo-1-(4-propoxyphenyl)-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.91 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.73 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.00 (t, J=7.4, 3H),1.44-1.62 (m, 2H), 1.68-1.83 (m, 2H), 2.06 (s, 3H), 2.46-2.54 (m, 2H),3.86 (s, 2H), 3.98 (t, J=6.4, 2H), 6.99-7.75 (m, 12H), 12.38 (s, 1H)

2-Methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-propoxyphenyl)-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-propoxyphenyl)-6-propylpyrimidin-4(3H)-one    sodium salt-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-propoxyphenyl)-6-propylpyrimidin-4(3H)-one    potassium salt-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-propoxyphenyl)-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-propoxyphenyl)-6-propylpyrimidin-4(3H)-one    hydrochloride-   2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-propoxyphenyl)-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 2503-(4-isopropoxy-3-methylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

250a)4′-{[1-(4-isopropoxy-3-methylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-isopropoxy-3-methylphenyl)boronic acid (1.0 g),triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was diluted with ethyl acetate, the insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (1.34 g, 94%).

¹H NMR (300 MHz, CDCl₃) δ 0.97-1.03 (m, 3H), 1.34 (d, J=6.1, 3H), 1.38(d, J=6.1, 3H), 1.60-1.78 (m, 2H), 2.18 (s, 3H), 2.22 (s, 3H), 2.58-2.72(m, 2H), 3.97 (s, 2H), 4.45-4.65 (m, 1H), 6.86-7.78 (m, 11H)

250b)3-(4-isopropoxy-3-methylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.9 g), sodium hydrogencarbonate (2.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-isopropoxy-3-methylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.34 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.55g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.09 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4, 3H), 1.30 (d, J=3.4, 3H),1.32 (d, J=3.4, 3H), 1.45-1.62 (m, 2H), 2.07 (s, 3H), 2.15 (s, 3H),2.47-2.55 (m, 2H), 3.86 (s, 2H), 4.56-4.75 (m, 1H), 7.01-7.74 (m, 11H),12.38 (s, 1H)

Example 2513-(4-isobutylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

251a)4′-{[1-(4-isobutylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-isobutylphenyl)boronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride(10 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred at room temperature for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (1.34 g, 97%).

¹H NMR (300 MHz, CDCl₃) δ 0.92 (d, J=6.8, 6H), 1.01 (t, J=7.4, 3H),1.61-1.77 (m, 2H), 1.80-1.98 (m, 1H), 2.16 (s, 3H), 2.53 (d, J=7.2, 2H),2.60-2.70 (m, 2H), 3.97 (s, 2H), 7.06-7.78 (m, 12H)

251b)3-(4-isobutylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.9 g), sodium hydrogencarbonate (2.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-isobutylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.34 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.55g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.60 g, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80-0.94 (m, 9H), 1.42-1.66 (m, 2H),1.80-1.97 (m, 1H), 2.05 (s, 3H), 2.47-2.59 (m, 4H), 3.87 (s, 2H),7.16-7.75 (m, 12H), 12.39 (s, 1H)

Example 2523-(4-isobutoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

252a)4′-{[1-(4-isobutoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-isobutoxyphenyl)boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylenechloride (10 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred at room temperature for 2 days. The reaction mixture wasdiluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.30 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.2, 3H), 1.03 (d, J=6.4, 6H),1.59-1.77 (m, 2H), 2.04-2.16 (m, 1H), 2.18 (s, 3H), 2.65 (dd, J=9.1,6.8, 2H), 3.75 (d, J=6.4, 2H), 3.97 (s, 2H), 6.94-7.79 (m, 12H)

252b)3-(4-isobutoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.9 g), sodium hydrogencarbonate (2.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-isobutoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.30 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.55g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (1.07 g, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.00 (d, J=6.8, 6H),1.46-1.62 (m, 2H), 1.96-2.12 (m, 1H), 2.06 (s, 3H), 2.46-2.54 (m, 2H),3.80 (d, J=6.4, 2H), 3.86 (s, 2H), 7.00-7.73 (m, 12H), 12.38 (s, 1H)

Example 2533-(4-isopropylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

253a)4′-{[1-(4-isopropylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-isopropylphenyl)boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylenechloride (10 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred at room temperature for 2 days. The reaction mixture wasdiluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.21 g, 90%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.27 (d, J=7.2, 6H),1.60-1.79 (m, 2H), 2.17 (s, 3H), 2.55-2.78 (m, 2H), 2.85-3.09 (m, 1H),3.97 (s, 2H), 7.01-7.83 (m, 12H)

253b)3-(4-isopropylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.82 g), sodium hydrogencarbonate (2.64 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-isopropylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.21 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.51g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.90 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.25 (d, J=6.8, 6H),1.46-1.62 (m, 2H), 2.05 (s, 3H), 2.50-2.55 (m, 2H), 2.87-3.06 (m, 1H),3.86 (s, 2H), 7.16-7.74 (m, 12H), 12.38 (s, 1H)

Example 2543-(4-tert-butylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

254a)4′-{[1-(4-tert-butylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-tert-butylphenyl)boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylenechloride (10 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred at room temperature for 2 days. The reaction mixture wasdiluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.12 g, 81%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.4, 3H), 1.35 (s, 9H), 1.59-1.80(m, 2H), 2.17 (s, 3H), 2.56-2.73 (m, 2H), 3.97 (s, 2H), 7.03-7.79 (m,12H)

254b)3-(4-tert-butylphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.8 g), sodium hydrogencarbonate (2.6 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-tert-butylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.12 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.51g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.91 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.33 (s, 9H), 1.42-1.64(m, 2H), 2.05 (s, 3H), 2.49-2.57 (m, 2H), 3.86 (s, 2H), 7.18-7.73 (m,12H), 12.38 (s, 1H)

Example 2553-[4-(cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

255a)4′-({1-[4-(cyclobutyloxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and bromocyclobutane (1.1 mL) in N,N-dimethylformamide (10 mL)was added cesium carbonate (1.5 g), and the mixture was stirred at 80°C. for 5 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.02 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.61-1.98 (m, 4H),2.14-2.27 (m, 2H), 2.17 (s, 3H), 2.39-2.53 (m, 2H), 2.65 (dd, J=9.8,5.7, 2H), 3.96 (s, 2H), 4.58-4.74 (m, 1H), 6.87-7.78 (m, 12H)

255b)3-[4-(cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.45 g), sodium hydrogencarbonate (2.10 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(cyclobutyloxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.02 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.41g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.73 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.46-1.90 (m, 4H),1.97-2.14 (m, 2H), 2.06 (s, 3H), 2.41-2.54 (m, 4H), 3.86 (s, 2H),4.67-4.82 (m, 1H), 6.92-7.75 (m, 12H), 12.38 (s, 1H)

3-[4-(Cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-[4-(cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-[4-(cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-[4-(cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-[4-(cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-[4-(cyclobutyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 2563-[4-(1-ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

256a)4′-({1-[4-(1-ethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and 3-bromopentane (1.40 mL) in N,N-dimethylformamide (10 mL)was added cesium carbonate (1.5 g), and the mixture was stirred at 80°C. for 5 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the aqueous layerwas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.98 g, 84%).

¹H NMR (300 MHz, CDCl₃) δ 0.91-1.05 (m, 6H), 1.62-1.76 (m, 6H), 2.19 (s,3H), 2.59-2.71 (m, 2H), 3.97 (s, 2H), 4.10-4.18 (m, 1H), 6.94-7.79 (m,12H)

256b)3-[4-(1-ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.45 g), sodium hydrogencarbonate (2.10 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(1-ethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.98 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.41g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.77 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.78-0.99 (m, 9H), 1.44-1.72 (m, 6H), 2.07(s, 3H), 2.46-2.55 (m, 2H), 3.86 (s, 2H), 4.21-4.34 (m, 1H), 6.93-7.75(m, 12H), 12.38 (s, 1H)

3-[4-(1-Ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-[4-(1-ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-[4-(1-ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-[4-(1-ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-[4-(1-ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-[4-(1-ethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 2572-methyl-3-[4-(methylthio)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

257a)4′-({2-methyl-1-[4-(methylthio)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), [4-(methylthio)phenyl]boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylenechloride (10 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred at room temperature for 2 days. The reaction mixture wasdiluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (0.24 g, 17%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.62-1.76 (m, 2H), 2.18(s, 3H), 2.51 (s, 3H), 2.60-2.71 (m, 2H), 3.96 (s, 2H), 7.05-7.80 (m,12H)

257b)2-methyl-3-[4-(methylthio)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogencarbonate (0.51 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({2-methyl-1-[4-(methylthio)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (3 mL). N,N′-carbonyldiimidazole (0.10g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.091 mL) were added,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.17 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.46-1.62 (m, 2H), 2.07(s, 3H), 2.48-2.52 (m, 2H), 2.53 (s, 3H), 3.86 (s, 2H), 7.17-7.73 (m,12H), 12.38 (s, 1H)

Example 2582-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(trifluoromethoxy)phenyl]pyrimidin-4(3H)-one

258a)4′-({2-methyl-6-oxo-4-propyl-1-[4-(trifluoromethoxy)phenyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), [4-(trifluoromethoxy)phenyl]boronic acid (1.0 g), triethylamine(2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) inmethylene chloride (10 mL) was added copper(II) acetate (1.0 g), and themixture was stirred at room temperature for 2 days. The reaction mixturewas diluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.12 g, 76%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.3, 3H), 1.62-1.78 (m, 2H), 2.17(s, 3H), 2.60-2.73 (m, 2H), 3.96 (s, 2H), 7.22-7.79 (m, 12H)

258b)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(trifluoromethoxy)phenyl]pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.54 g), sodium hydrogencarbonate (2.23 g) and dimethyl sulfoxide (11 mL) was stirred at 40° C.for 30 min,4′-({2-methyl-6-oxo-4-propyl-1-[4-(trifluoromethoxy)phenyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.12 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.43g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.40 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (1.04 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.4, 3H), 1.45-1.64 (m, 2H), 2.07(s, 3H), 2.49-2.57 (m, 2H), 3.87 (s, 2H), 7.15-7.76 (m, 12H), 12.39 (s,1H)

Example 2592-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-phenoxyphenyl)-6-propylpyrimidin-4(3H)-one

259a)4′-{[2-methyl-6-oxo-1-(4-phenoxyphenyl)-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-phenoxyphenyl)boronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylene chloride(10 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred at room temperature for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (1.37 g, 92%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.62-1.82 (m, 2H), 2.20(s, 3H), 2.52-2.78 (m, 2H), 3.97 (s, 2H), 6.89-7.83 (m, 17H)

259b)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-phenoxyphenyl)-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.86 g), sodium hydrogencarbonate (2.70 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-6-oxo-1-(4-phenoxyphenyl)-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.37 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.52g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.48 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (1.15 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.46-1.64 (m, 2H), 2.10(s, 3H), 2.48-2.57 (m, 2H), 3.87 (s, 2H), 7.05-7.74 (m, 17H), 12.38 (s,1H)

Example 2603-(4-tert-butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

260a)4′-{[1-(4-tert-butoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-tert-butoxyphenyl)boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylenechloride (10 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred at room temperature for 2 days. The reaction mixture wasdiluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.39 g, 97%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.39 (s, 9H), 1.61-1.77(m, 2H), 2.16 (s, 3H), 2.59-2.69 (m, 2H), 3.97 (s, 2H), 7.08-7.78 (m,12H)

260b)3-(4-tert-butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.97 g), sodium hydrogencarbonate (2.86 g) and dimethyl sulfoxide (14 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-tert-butoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.39 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (14 mL). N,N′-carbonyldiimidazole (0.55g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (1.21 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.35 (s, 9H), 1.44-1.63(m, 2H), 2.06 (s, 3H), 2.51-2.55 (m, 2H), 3.87 (s, 2H), 7.04-7.73 (m,12H), 12.38 (s, 1H)

Example 2613-(3-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

261a)4′-{[1-(3-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (3-isopropoxyphenyl)boronic acid (1.0 g), triethylamine (2.0mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) in methylenechloride (10 mL) was added copper(II) acetate (1.0 g), and the mixturewas stirred at room temperature for 2 days. The reaction mixture wasdiluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.24 g, 89%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.33 (d, J=6.0, 3H), 1.35(d, J=6.0, 3H), 1.62-1.77 (m, 2H), 2.20 (s, 3H), 2.57-2.72 (m, 2H), 3.97(s, 2H), 4.49-4.62 (m, 1H), 6.70-7.78 (m, 12H)

261b)3-(3-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.81 g), sodium hydrogencarbonate (2.62 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C.for 30 min,4′-{[1-(3-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.24 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (13 mL). N,N′-carbonyldiimidazole (0.51g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.47 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.96 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.26 (d, J=4.0, 3H),1.28 (d, J=4.0, 3H), 1.44-1.63 (m, 2H), 2.09 (s, 3H), 2.49-2.55 (m, 2H),3.87 (s, 2H), 4.58-4.74 (m, 1H), 6.83-7.74 (m, 12H), 12.38 (s, 1H)

Example 2623-[4-(isopropylthio)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

262a)4′-({1-[4-(isopropylthio)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), [4-(isopropylthio)phenyl]boronic acid (1.0 g), triethylamine(2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0 g) inmethylene chloride (10 mL) was added copper(II) acetate (1.0 g), and themixture was stirred at room temperature for 2 days. The reaction mixturewas diluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.20 g, 84%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.34 (d, J=6.8, 6H),1.62-1.77 (m, 2H), 2.17 (s, 3H), 2.59-2.71 (m, 2H), 3.35-3.55 (m, 1H),3.97 (s, 2H), 7.10-7.20 (m, 2H), 7.36-7.78 (m, 10H)

262b)3-[4-(isopropylthio)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogencarbonate (2.46 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(isopropylthio)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (12 mL). N,N′-carbonyldiimidazole (0.48g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.44 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.90 g, 67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.29 (d, J=6.6, 6H),1.45-1.64 (m, 2H), 2.07 (s, 3H), 2.49-2.56 (m, 2H), 3.51-3.70 (m, 1H),3.87 (s, 2H), 7.17-7.73 (m, 12H), 12.38 (s, 1H)

Example 263

3-[4-(isopropylsulfonyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-[4-(isopropylthio)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.28 g) in acetonitrile (3 mL) was added 3-chlorobenzenecarboperoxoicacid (0.26 g), and the mixture was stirred at 0° C. for 3 hr. Ethylacetate, water and sodium thiosulfate were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.21 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.3, 3H), 1.20 (d, J=6.8, 6H),1.47-1.65 (m, 2H), 2.07 (s, 3H), 2.48-2.58 (m, 2H), 3.32 (m, 1H), 3.88(s, 2H), 7.16-8.08 (m, 12H), 12.38 (s, 1H)

Example 264N,N-dimethyl-4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]benzamide

264a)4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]-N,N-dimethylbenzamide

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), {4-[(dimethylamino)carbonyl]phenyl}boronic acid (1.0 g),triethylamine (2.0 mL), pyridine (1.0 mL) and molecular sieves 4 A (3.0g) in methylene chloride (10 mL) was added copper(II) acetate (1.0 g),and the mixture was stirred at room temperature for 2 days. The reactionmixture was diluted with ethyl acetate, the insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.92 g, 64%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.61-1.79 (m, 2H), 2.16(s, 3H), 2.60-2.71 (m, 2H), 3.01 (s, 3H), 3.13 (s, 3H), 3.97 (s, 2H),7.27-7.78 (m, 12H)

264b)N,N-dimethyl-4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]benzamide

A mixture of hydroxylammonium chloride (1.30 g), sodium hydrogencarbonate (1.88 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]-N,N-dimethylbenzamide(0.92 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (12 mL). N,N′-carbonyldiimidazole (0.48g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.44 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.37 g, 36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.3, 3H), 1.45-1.65 (m, 2H), 2.08(s, 3H), 2.50-2.59 (m, 2H), 2.94 (s, 3H), 3.01 (s, 3H), 3.88 (s, 2H),7.16-7.73 (m, 12H), 12.38 (s, 1H)

Example 2653-[4-(cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

265a)4′-({1-[4-(cyclopropyloxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and bromocyclopropane (1.8 mL) in N,N-dimethylformamide (10 mL)was added cesium carbonate (1.5 g), and the mixture was stirred at 80°C. for 5 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.097 g, 9%).

¹H NMR (300 MHz, CDCl₃) δ 0.76-0.84 (m, 4H), 1.01 (t, J=7.3, 3H),1.61-1.77 (m, 2H), 2.18 (s, 3H), 2.59-2.70 (m, 2H), 3.71-3.80 (m, 1H),3.97 (s, 2H), 7.09-7.78 (m, 12H)

265b)3-[4-(cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.014 g), sodium hydrogencarbonate (0.02 g) and dimethyl sulfoxide (1 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(cyclopropyloxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.097 g) was added, and the mixture was stirred at 90° C. for 18 hr.The reaction mixture was allowed to cool to room temperature, ethylacetate and water were added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was dissolved in tetrahydrofuran (1 mL).N,N′-carbonyldiimidazole (0.040 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.040 mL) were added, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.046 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.59-0.84 (m, 4H), 0.89 (t, J=7.3, 3H),1.45-1.62 (m, 2H), 2.07 (s, 3H), 2.49-2.56 (m, 2H), 3.86 (s, 2H),3.87-3.95 (m, 1H), 7.12-7.75 (m, 12H), 12.38 (br s, 1H)

3-[4-(Cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-[4-(cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-[4-(cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-[4-(cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-[4-(cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-[4-(cyclopropyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 2663-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

266a) methyl2-(4-{5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}phenoxy)-2-methylpropanoate

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and methyl 2-bromo-2-methylpropanoate (1.25 g) inN,N-dimethylformamide (10 mL) was added cesium carbonate (1.5 g), andthe mixture was stirred at 80° C. for 5 hr. The reaction mixture wasallowed to cool to room temperature, ethyl acetate and water were added,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated and the residue was purified by silica gelcolumn chromatography to give the title compound as a pale-yellowviscous substance (0.97 g, 79%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.4, 3H), 1.63 (s, 6H), 1.64-1.76(m, 2H), 2.15 (s, 3H), 2.59-2.69 (m, 2H), 3.78 (s, 3H), 3.96 (s, 2H),6.89-7.79 (m, 12H)

266b)4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of methyl2-(4-{5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}phenoxy)-2-methylpropanoate(0.97 g) in tetrahydrofuran (10 mL) was added lithium tetrahydroboron(0.048 g), and the mixture was stirred at room temperature for 24 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.49 g, 53%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.33 (s, 6H), 1.61-1.77(m, 2H), 2.17 (s, 3H), 2.61-2.70 (m, 2H), 3.56-3.64 (m, 3H), 3.97 (s,2H), 7.10-7.78 (m, 12H)

266c)3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogencarbonate (0.98 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.49 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.19g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.14 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.25 (s, 6H), 1.45-1.63(m, 2H), 2.06 (s, 3H), 2.50-2.56 (m, 2H), 3.42 (d, J=5.5, 2H), 3.87 (s,2H), 4.94 (t, J=5.5, 1H), 7.09-7.73 (m, 12H), 12.36 (br s, 1H)

Example 2673-[4-(1-hydroxyethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

267a)4′-{[1-(4-acetylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(3.0 g), (4-acetylphenyl)boronic acid (3.0 g), triethylamine (6.0 mL),pyridine (3.0 mL) and molecular sieves 4 A (6.0 g) in methylene chloride(30 mL) was added copper(II) acetate (3.0 g), and the mixture wasstirred at room temperature for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (2.34 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.78-0.98 (m, 3H), 1.46-1.70 (m, 2H), 2.07(s, 3H), 2.52-2.60 (m, 2H), 2.64 (s, 3H), 3.93 (s, 2H), 7.33-8.16 (m,12H)

267b)4′-({1-[4-(1-hydroxyethyl)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-acetylphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) in methanol (10 mL) was added sodium tetrahydroboron (0.11 g),and the mixture was stirred at 0° C. for 2 hr. Ethyl acetate and waterwere added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (1.02 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.51 (d, J=6.4, 3H),1.61-1.78 (m, 2H), 2.16 (s, 3H), 2.59-2.73 (m, 2H), 3.97 (s, 2H),4.88-5.03 (m, 1H), 7.15-7.80 (m, 12H)

267c)3-[4-(1-hydroxyethyl)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (3.30 g), sodium hydrogencarbonate (4.80 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(1-hydroxyethyl)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(2.22 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.77g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.85 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.57 g, 23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.37 (d, J=6.4, 3H),1.46-1.63 (m, 2H), 2.05 (s, 3H), 2.50-2.55 (m, 2H), 3.87 (s, 2H),4.74-4.86 (m, 1H), 5.28 (d, J=4.2, 1H), 7.18-7.72 (m, 12H), 12.36 (s,1H)

Example 268

3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.40 g), sodium hydrogencarbonate (2.00 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.87 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.39g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.48 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.2, 3H), 1.45-1.63 (m, 2H), 2.06(s, 3H), 2.46-2.54 (m, 2H), 3.86 (s, 2H), 6.79-7.76 (m, 12H), 9.78 (s,1H), 12.36 (s, 1H)

Example 2693-(3-fluoro-4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

269a)4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[1-(3-fluoro-4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(6.40 g) in methylene chloride (30 mL) was added boron tribromide (1.0 Mmethylene chloride solution, 27 mL), and the mixture was stirred at roomtemperature for 2 days. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow solid (6.27 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.3, 3H), 1.56-1.80 (m, 2H), 2.19(s, 3H), 2.56-2.74 (m, 2H), 4.01 (s, 2H), 6.69-8.05 (m, 12H)

269b)3-(3-fluoro-4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.40 g), sodium hydrogencarbonate (2.00 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.91 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.39g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.66 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.2, 3H), 1.41-1.64 (m, 2H), 2.09(s, 3H), 2.42-2.55 (m, 2H), 3.86 (s, 2H), 6.95-7.72 (m, 11H), 10.25 (s,1H), 12.36 (s, 1H)

Example 270

methyl2-methyl-2-{4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]phenoxy}propanoate

A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogencarbonate (1.00 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min, methyl2-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate(0.87 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.20g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.24 g, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.44-1.65 (m, 8H), 2.05(s, 3H), 2.45-2.56 (m, 2H), 3.72 (s, 3H), 3.86 (s, 2H), 6.83-7.76 (m,12H), 12.36 (s, 1H)

Example 2713-(4-sec-butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

271a)4′-{[1-(4-sec-butoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and 2-bromobutane (0.66 mL) in N,N-dimethylformamide (10 mL) wasadded cesium carbonate (1.5 g), and the mixture was stirred at 80° C.for 48 hr. The reaction mixture was allowed to cool to room temperature,ethyl acetate and water were added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.85 g, 76%).

¹H NMR (300 MHz, CDCl₃) δ 0.91-1.06 (m, 6H), 1.32 (d, J=6.2, 3H),1.58-1.86 (m, 4H), 2.18 (s, 3H), 2.57-2.72 (m, 2H), 3.97 (s, 2H),4.23-4.41 (m, 1H), 6.89-7.81 (m, 12H)

271b)3-(4-sec-butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.21 g), sodium hydrogencarbonate (1.76 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-sec-butoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.34 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (8 mL). N,N′-carbonyldiimidazole (0.34g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.47 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.99 (m, 6H), 1.26 (d, J=6.1, 3H),1.45-1.78 (m, 4H), 2.45-2.54 (m, 2H), 3.86 (s, 2H), 4.36-4.51 (m, 1H),6.94-7.75 (m, 12H), 12.36 (s, 1H)

3-(4-sec-Butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(4-sec-butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-(4-sec-butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-(4-sec-butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-(4-sec-butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-(4-sec-butoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 2723-[4-(cyclopropylmethoxy)-3-fluorophenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

272a)4′-({1-[4-(cyclopropylmethoxy)-3-fluorophenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and (bromomethyl)cyclopropane (0.64 mL) in N,N-dimethylformamide(10 mL) was added cesium carbonate (1.5 g), and the mixture was stirredat 80° C. for 48 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.95 g, 85%).

¹H NMR (300 MHz, CDCl₃) δ 0.33-0.42 (m, 2H), 0.62-0.73 (m, 2H), 1.01 (t,J=7.3, 3H), 1.26-1.43 (m, 1H), 1.62-1.77 (m, 2H), 2.19 (s, 3H),2.59-2.70 (m, 2H), 3.84-4.03 (m, 4H), 6.88-7.83 (m, 11H)

272b)3-[4-(cyclopropylmethoxy)-3-fluorophenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.31 g), sodium hydrogencarbonate (1.90 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(cyclopropylmethoxy)-3-fluorophenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.95 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.74 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.31-0.41 (m, 2H), 0.56-0.64 (m, 2H), 0.88(t, J=7.2, 3H), 1.21-1.34 (m, 1H), 1.45-1.61 (m, 2H), 2.08 (s, 3H),2.45-2.53 (m, 2H), 3.86 (s, 2H), 3.91-4.02 (m, 2H), 7.10-7.74 (m, 11H),12.37 (s, 1H)

Example 2733-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

273a) methyl2-(4-{5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}phenoxy)propanoate

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.0 g) and methyl 2-bromopropanoate (2.50 g) in N,N-dimethylformamide(20 mL) was added cesium carbonate (3.0 g), and the mixture was stirredat 80° C. for 15 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (2.12 g, 89%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.61-1.76 (m, 5H), 2.16(s, 3H), 2.57-2.71 (m, 2H), 3.78 (s, 3H), 3.96 (s, 2H), 4.78 (q, J=6.8,1H), 6.89-7.82 (m, 12H)

273b)4′-({1-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of methyl2-(4-{5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl}phenoxy]propanoate(1.60 g) in tetrahydrofuran (30 mL) was added lithium tetrahydroboron(80 mg), and the mixture was stirred at room temperature for 40 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.34 g, 88%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.30 (d, J=6.2, 3H),1.61-1.78 (m, 2H), 2.05-2.15 (m, 1H), 2.19 (s, 3H), 2.60-2.71 (m, 2H),3.69-3.82 (m, 2H), 3.97 (s, 2H), 4.45-4.62 (m, 1H), 6.99-7.79 (m, 12H)

273c)3-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.36 g), sodium hydrogencarbonate (2.18 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.64 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.20 g, 27%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.24 (d, J=6.1, 3H),1.47-1.61 (m, 2H), 2.07 (s, 3H), 2.47-2.54 (m, 2H), 3.44-3.64 (m, 2H),3.86 (s, 2H), 4.42-4.54 (m, 1H), 4.88 (t, J=5.5, 1H), 7.02-7.73 (m,12H), 12.32 (s, 1H)

Example 2743-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

274a)4′-({1-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.69 g) in N,N-dimethylformamide (7 mL) were added 60% sodium hydride(0.065 g) and then methyl iodide at 0° C., and the mixture was stirredfor 1 hr. Ethyl acetate and water were added to the reaction mixture,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated and the residue was purified by silica gelcolumn chromatography to give the title compound as a pale-yellowviscous substance (0.52 g, 74%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.34 (s, 6H), 1.62-1.77(m, 2H), 2.15 (s, 3H), 2.60-2.69 (m, 2H), 3.38 (s, 2H), 3.43 (s, 3H),3.97 (s, 2H), 7.06-7.78 (m, 12H)

274b)3-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogencarbonate (1.26 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.52 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.21g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.27 g, 41%).

1H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.28 (s, 6H), 1.47-1.62(m, 2H), 2.06 (s, 3H), 2.47-2.55 (m, 2H), 3.33 (s, 3H), 3.36 (s, 2H),3.87 (s, 2H), 7.07-7.74 (m, 12H), 12.38 (s, 1H)

Example 2753-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

275a) 4-bromo-2-fluoro-1-[(2-methylprop-2-en-1-yl)oxy]benzene

To a solution of 4-bromo-2-fluorophenol (26.8 g) and3-chloro-2-methylprop-1-ene (13.7 mL) in acetone (420 mL) was addedpotassium carbonate (29 g), and the mixture was stirred at 70° C. for 15hr. The reaction mixture was allowed to cool to room temperature, waterwas added to the reaction mixture, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (29.9 g, 87%).

¹H NMR (300 MHz, CDCl₃) δ 1.83 (s, 3H), 4.48 (s, 2H), 5.04 (d, J=23.5,2H), 6.84 (t, J=8.9, 1H), 7.13-7.26 (m, 2H)

275b) 5-bromo-7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran

A solution of 4-bromo-2-fluoro-1-[(2-methylprop-2-en-1-yl)oxy]benzene(29.9 g) in N,N-diethylaniline (30 mL) was stirred at 190° C. for 5 hr.The mixture was allowed to cool to room temperature, and the reactionmixture was diluted with diisopropyl ether, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. The residuewas dissolved in toluene (240 mL), boron trifluoride diethyl ethercomplex was added, and the mixture was stirred at 60° C. for 15 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (18.9 g, 63%).

¹H NMR (300 MHz, CDCl₃) δ 1.51 (s, 6H), 3.04 (s, 2H), 6.97-7.24 (m, 2H)

275c) (7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid

To a solution of 5-bromo-7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran(18.9 g) in tetrahydrofuran (250 mL) was added butyllithium (53 mL, 1.60M hexane solution) under an argon atmosphere at −78° C., and the mixturewas stirred for 1 hr. Triisopropyl borate (21 mL) was added, and themixture was stirred for 12 hr while allowing to warm to roomtemperature. 1 M hydrochloric acid (150 mL) was added, and the mixturewas stirred for 1 hr, and extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (6.54 g, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.45 (s, 6H), 3.02-3.15 (m, 2H), 7.26-8.00(m, 4H)

275d)4′-{[1-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronicacid (1.22 g), triethylamine (2.0 mL), pyridine (1.0 mL) and molecularsieves 4 A (2.0 g) in methylene chloride (15 mL) was added copper(II)acetate (1.0 g), and the mixture was stirred at room temperature for 3days. The reaction mixture was diluted with ethyl acetate, the insolublematerial was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.20 g, 81%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.53 (s, 3H), 1.57 (s,3H), 1.64-1.76 (m, 2H), 2.22 (s, 3H), 2.61-2.69 (m, 2H), 3.04-3.18 (m,2H), 3.90-4.02 (m, 2H), 6.77-6.85 (m, 2H), 7.36-7.77 (m, 8H)

275e)3-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.95 g), sodium hydrogencarbonate (2.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.19 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the aqueous layer was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.49 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.95 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4, 3H), 1.42-1.62 (m, 8H), 2.11(s, 3H), 2.45-2.54 (m, 2H), 3.13 (s, 2H), 3.86 (s, 2H), 6.98-7.73 (m,10H), 12.36 (s, 1H)

3-(7-Fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-(7-fluoro-2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 276

3-{4-[2-fluoro-1-(fluoromethyl)ethoxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), 1,3-difluoropropan-2-ol (0.66 mL), triphenylphosphine (1.2 g)in tetrahydrofuran (7 mL) was added diisopropyl azodicarboxylate (0.90mL, 1.9 M toluene solution), and the mixture was stirred at roomtemperature for 1 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was crudely purifiedby silica gel column chromatography. This was added to a mixture ofhydroxylammonium chloride (1.21 g), sodium hydrogen carbonate (1.38 g)and dimethyl sulfoxide (8 mL), which had been stirred at 40° C. for 30min, and the mixture was stirred at 90° C. for 18 hr. The reactionmixture was allowed to cool to room temperature, ethyl acetate and waterwere added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.35 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.32 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.68 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.2, 3H), 1.46-1.62 (m, 2H), 2.07(s, 3H), 2.47-2.54 (m, 2H), 3.87 (s, 2H), 4.58-5.14 (m, 5H), 7.14-7.73(m, 12H), 12.37 (s, 1H)

Example 277

3-[4-(2-fluoro-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.65 g), 1-fluoropropan-2-ol (0.23 g), triphenylphosphine (0.78 g) intetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (0.59 mL,1.9 M toluene solution), and the mixture was stirred at room temperaturefor 2 hr. Ethyl acetate and water were added to the reaction mixture,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated and the residue was crudely purified bysilica gel column chromatography. This was added to a mixture ofhydroxylammonium chloride (1.24 g), sodium hydrogen carbonate (1.88 g)and dimethyl sulfoxide (8 mL), which had been stirred at 40° C. for 30min, and the mixture was stirred at 90° C. for 18 hr. The reactionmixture was allowed to cool to room temperature, ethyl acetate and waterwere added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wasdissolved in tetrahydrofuran (8 mL). N,N′-carbonyldiimidazole (0.48 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.47 g, 57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.27 (dd, J=6.4, 1.5,3H), 1.47-1.61 (m, 2H), 2.07 (s, 3H), 2.46-2.55 (m, 2H), 3.86 (s, 2H),4.39-4.92 (m, 3H), 7.04-7.72 (m, 12H), 12.36 (s, 1H)

3-[4-(2-Fluoro-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-[4-(2-fluoro-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-[4-(2-fluoro-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-[4-(2-fluoro-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-[4-(2-fluoro-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-[4-(2-fluoro-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 278

3-[4-(1-cyclopropylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.65 g), 1-cyclopropylethanol (0.26 g), triphenylphosphine (0.79 g) intetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (0.59 mL,1.9 M toluene solution), and the mixture was stirred at room temperaturefor 2 hr. Ethyl acetate and water were added to the reaction mixture,and the mixture was extracted with ethyl acetate. The organic layer waswashed with saturated brine and dried over anhydrous magnesium sulfate.The solvent was evaporated and the residue was crudely purified bysilica gel column chromatography. This was added to a mixture ofhydroxylammonium chloride (1.24 g), sodium hydrogen carbonate (1.88 g)and dimethyl sulfoxide (8 mL), which had been stirred at 40° C. for 30min, and the mixture was stirred at 90° C. for 18 hr. The reactionmixture was allowed to cool to room temperature, ethyl acetate and waterwere added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wasdissolved in tetrahydrofuran (8 mL). N,N′-carbonyldiimidazole (0.48 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.21 g, 25%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.25-0.59 (m, 4H), 0.89 (t, J=7.4, 3H),1.05-1.20 (m, 1H), 1.31 (d, J=6.1, 3H), 1.45-1.63 (m, 2H), 2.07 (s, 3H),2.47-2.53 (m, 2H), 3.86 (s, 2H), 3.96-4.09 (m, 1H), 6.97-7.73 (m, 12H),12.36 (s, 1H)

Example 2793-(4-ethoxy-3-fluorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

279a)4′-{[1-(4-ethoxy-3-fluorophenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and ethyl iodide (0.53 mL) in N,N-dimethylformamide (10 mL) wasadded cesium carbonate (1.44 g), and the mixture was stirred at 80° C.for 2 hr. The reaction mixture was allowed to cool to room temperature,ethyl acetate and water were added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.96 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.48 (t, J=7.1, 3H),1.60-1.77 (m, 2H), 2.19 (s, 3H), 2.59-2.71 (m, 2H), 3.96 (s, 2H), 4.15(q, J=7.0, 2H), 6.90-7.77 (m, 11H)

279b)3-(4-ethoxy-3-fluorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.40 g), sodium hydrogencarbonate (2.00 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-ethoxy-3-fluorophenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.96 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.42g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.76 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.38 (t, J=7.0, 3H),1.47-1.61 (m, 2H), 2.09 (s, 3H), 2.46-2.53 (m, 2H), 3.87 (s, 2H), 4.17(q, J=7.0, 2H), 7.12-7.74 (m, 11H), 12.38 (s, 1H)

Example 2803-[4-(cyclopropyloxy)-3-fluorophenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

280a)4′-({1-[4-(cyclopropyloxy)-3-fluorophenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and bromocyclopropane (1.8 mL) in N,N-dimethylformamide (10 mL)was added cesium carbonate (3.60 g), and the mixture was stirred at 150°C. for 2 days. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.15 g, 14%).

¹H NMR (300 MHz, CDCl₃) δ 0.78-0.90 (m, 4H), 0.97-1.04 (m, 3H),1.62-1.76 (m, 2H), 2.19 (d, J=3.4, 3H), 2.61-2.69 (m, 2H), 3.80-3.89 (m,1H), 3.92-4.02 (m, 2H), 6.82-7.78 (m, 11H)

280b)3-[4-(cyclopropyloxy)-3-fluorophenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.32 g), sodium hydrogencarbonate (0.52 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(cyclopropyloxy)-3-fluorophenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.15 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (3 mL). N,N′-carbonyldiimidazole (0.075g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.070 mL) were added,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as colorless crystals (0.077 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.69-0.95 (m, 7H), 1.43-1.61 (m, 2H), 2.09(s, 3H), 2.46-2.54 (m, 2H), 3.87 (s, 2H), 3.98-4.11 (m, 1H), 7.16-7.74(m, 11H), 12.38 (s, 1H)

Example 281

6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.56 g), sodium hydrogencarbonate (2.35 g) and dimethyl sulfoxide (14 mL) was stirred at 40° C.for 30 min,4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.48g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.46 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.37 g, 31%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (t, J=7.2, 3H), 1.21-1.49 (m, 4H), 2.24(s, 3H), 2.38-2.49 (m, 2H), 3.81 (s, 2H), 7.17-7.72 (m, 9H), 12.32 (s,1H)

Example 2826-butyl-3-(cyclopropylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

282a)4′-{[4-butyl-1-(cyclopropylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.75 g) and (bromomethyl)cyclopropane (1.36 mL) inN,N-dimethylformamide (10 mL) was added 60% sodium hydride (0.17 g), andthe mixture was stirred at room temperature for 15 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedand the residue was purified by silica gel column chromatography to givethe title compound as a pale-yellow viscous substance (0.55 g, 63%).

¹H NMR (300 MHz, CDCl₃) δ 0.37-0.68 (m, 4H), 0.91 (t, J=7.3, 3H),1.08-1.64 (m, 5H), 2.53-2.62 (m, 2H), 2.58 (s, 3H), 3.94-4.01 (m, 2H),3.96 (s, 2H), 7.31-7.78 (m, 8H)

282b)6-butyl-3-(cyclopropylmethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.74 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(cyclopropylmethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.55 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (6 mL). N,N′-carbonyldiimidazole (0.29g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.089 g, 14%).

¹H NMR (300 MHz, CDCl₃) δ 0.28-0.70 (m, 4H), 0.93 (t, J=7.3, 3H),1.02-2.11 (m, 5H), 2.51-2.69 (m, 2H), 2.55 (s, 3H), 3.86-3.96 (m, 4H),7.18-7.88 (m, 9H)

Example 2836-butyl-3-isopropyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

283a)4′-[(4-butyl-1-isopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.00 g) and 2-iodopropane (2.8 mL) in N,N-dimethylformamide (20 mL) wasadded 60% sodium hydride (0.34 g), and the mixture was stirred at roomtemperature for 15 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (0.23 g, 10%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.3, 3H), 1.27-1.68 (m, 4H), 1.60(d, J=1.9, 6H), 2.47-2.60 (m, 2H), 2.55 (s, 3H), 3.93 (s, 2H), 4.63 (s,1H), 7.29-7.78 (m, 8H)

283b)6-butyl-3-isopropyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.32 g), sodium hydrogencarbonate (0.48 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-[(4-butyl-1-isopropyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.23 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.092g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.085 mL) were added,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.14 g, 53%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.3, 3H), 1.29-1.65 (m, 4H), 1.53(d, J=6.8, 6H), 2.47-2.58 (m, 2H), 2.52 (s, 3H), 3.84 (s, 2H), 4.42-4.68(m, 1H), 7.17-7.87 (m, 9H)

Example 2846-butyl-2,3-dimethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

284a)4′-[(4-butyl-1,2-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.00 g) and iodomethane (0.87 mL) in N,N-dimethylformamide (10 mL) wasadded 60% sodium hydride (0.17 g), and the mixture was stirred at roomtemperature for 15 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (0.95 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.3, 3H), 1.30-1.61 (m, 4H), 2.51(s, 3H), 2.54-2.64 (m, 2H), 3.53 (s, 3H), 3.96 (s, 2H), 7.32-7.78 (m,8H)

284b)6-butyl-2,3-dimethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.40 g), sodium hydrogencarbonate (2.10 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C.for 30 min,4′-[(4-butyl-1,2-dimethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.95 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.32g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.64 g, 59%).

¹H NMR (300 MHz, CDCl₃) δ 0.92 (t, J=7.3, 3H), 1.27-1.67 (m, 4H), 2.50(s, 3H), 2.52-2.65 (m, 2H), 3.47 (s, 3H), 3.87 (s, 2H), 3.93-4.05 (m,1H), 7.15-7.84 (m, 8H)

Example 2856-butyl-2-(2-phenylethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

285a)4′-{[4-butyl-6-oxo-2-(2-phenylethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of methyl2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (0.70 g) and3-phenylpropanimidamide (0.63 g) in methanol (10 mL) was added 28%sodium methoxide-methanol solution (1.7 mL), and the mixture was stirredat room temperature for 24 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (0.71 g, 79%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (t, J=7.3, 3H), 1.21-1.71 (m, 4H),2.53-2.70 (m, 2H), 2.84-3.21 (m, 4H), 3.98 (s, 2H), 6.98-7.91 (m, 13H),12.73 (s, 1H)

285b)6-butyl-2-(2-phenylethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogencarbonate (1.34 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-6-oxo-2-(2-phenylethyl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.71 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.30g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.43 g, 53%).

¹H NMR (300 MHz, CDCl₃) δ 0.87 (t, J=7.2, 3H), 1.21-1.54 (m, 4H),2.44-2.61 (m, 2H), 2.77-2.90 (m, 2H), 2.94-3.07 (m, 2H), 3.77 (s, 2H),7.10-7.84 (m, 13H), 11.08 (s, 1H), 11.63 (s, 1H)

Example 2862-butyl-5-(2-hydroxy-3,3-dimethylbutyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

286a) ethyl 2-acetyl-5,5-dimethyl-4-oxohexanoate

To a solution of sodium 4-ethoxy-4-oxobut-2-en-2-olate (1.50 g) inN,N-dimethylformamide (50 mL) was added 1-bromo-3,3-dimethylbutan-2-one(2.0 mL), and the mixture was stirred at room temperature for 1 hr.Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (1.51 g, 53%).

¹H NMR (300 MHz, CDCl₃) δ 1.17 (s, 9H), 1.28 (t, J=7.2, 3H), 2.37 (s,3H), 2.96-3.06 (m, 1H), 3.17-3.29 (m, 1H), 4.01 (dd, J=8.3, 5.7, 1H),4.19 (q, J=7.2, 2H)

286b) 2-butyl-5-(3,3-dimethyl-2-oxobutyl)-6-methylpyrimidin-4(3H)-one

To a solution of ethyl 2-acetyl-5,5-dimethyl-4-oxohexanoate (1.04 g) andpentanimidamide (0.89 g) in methanol (10 mL) was added 28% sodiummethoxide-methanol solution (3.7 mL), and the mixture was stirred atroom temperature for 24 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (0.34 g, 36%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (t, J=7.3, 3H), 1.26 (s, 9H), 1.30-1.50(m, 2H), 1.62-1.79 (m, 2H), 2.21 (s, 3H), 2.49-2.66 (m, 2H), 3.73 (s,2H), 12.59 (br s, 1H)

286c)4′-{[2-butyl-5-(3,3-dimethyl-2-oxobutyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of2-butyl-5-(3,3-dimethyl-2-oxobutyl)-6-methylpyrimidin-4(3H)-one (0.48 g)and 4′-(bromomethyl)biphenyl-2-carbonitrile (0.99 g) inN,N-dimethylformamide (9 mL) was added potassium carbonate (0.75 g), andthe mixture was stirred at 80° C. for 24 hr. The reaction mixture wasallowed to cool to room temperature, ethyl acetate and water were added,and the aqueous layer was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (0.33 g, 40%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.3, 3H), 1.27 (s, 9H), 1.30-1.78(m, 4H), 2.60-2.71 (m, 2H), 3.82 (s, 2H), 5.34 (s, 2H), 7.20-7.83 (m,8H)

286d)4′-{[2-butyl-5-(2-hydroxy-3,3-dimethylbutyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[2-butyl-5-(3,3-dimethyl-2-oxobutyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.33 g) in ethanol (4 mL) was added sodium tetrahydroboron (0.053 g),and the mixture was stirred at room temperature for 3 hr. Ethyl acetateand water were added to the reaction mixture, and the aqueous layer wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow viscoussubstance (0.20 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (t, J=7.3, 3H), 1.00 (s, 9H), 1.31-1.74(m, 4H), 2.34 (s, 3H), 2.62-2.85 (m, 4H), 3.32-3.45 (m, 1H), 3.59-3.67(m, 1H), 5.36 (s, 2H), 7.24-7.80 (m, 8H)

286e)2-butyl-5-(2-hydroxy-3,3-dimethylbutyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogencarbonate (0.36 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-5-(2-hydroxy-3,3-dimethylbutyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.20 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (3 mL). N,N′-carbonyldiimidazole (0.057g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.052 mL) were added,and the mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.082 g, 37%).

¹H NMR (300 MHz, CDCl₃) δ 0.83-0.97 (m, 12H), 1.32-1.81 (m, 4H), 2.30(s, 3H), 2.50-2.81 (m, 4H), 3.21-3.39 (m, 1H), 3.67-3.82 (m, 1H),5.17-5.38 (m, 2H), 7.18-7.83 (m, 8H), 8.67 (s, 1H)

Example 2875-benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

287a) 5-benzyl-6-methyl-2-propylpyrimidin-4(3H)-one

To a solution of ethyl 2-benzyl-3-oxobutanoate (2.13 mL) andbutanimidamide hydrochloride (2.05 g) in methanol (50 mL) was added 28%sodium methoxide-methanol solution (5.8 g), and the mixture was stirredat room temperature for 24 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.61 g, 66%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.3, 3H), 1.69-1.86 (m, 2H), 2.34(s, 3H), 2.52-2.62 (m, 2H), 3.89 (s, 2H), 7.12-7.30 (m, 5H), 12.99 (s,1H)

287b)4′-[(5-benzyl-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of 5-benzyl-6-methyl-2-propylpyrimidin-4(3H)-one (0.80 g)and 4′-(bromomethyl)biphenyl-2-carbonitrile (1.08 g) inN,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.17 g), andthe mixture was stirred at room temperature for 3 hr. Ethyl acetate andwater were added to the reaction mixture, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedand the residue was purified by silica gel column chromatography to givethe title compound as a pale-yellow viscous substance (0.61 g, 35%).

¹H NMR (300 MHz, CDCl₃) δ 0.98 (t, J=7.4, 3H), 1.64-1.82 (m, 2H), 2.34(s, 3H), 2.60-2.70 (m, 2H), 3.95 (s, 2H), 5.37 (s, 2H), 7.08-7.83 (m,13H)

287c)5-benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.20 g), sodium hydrogencarbonate (1.80 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(5-benzyl-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.93 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added to the reaction mixture, and the aqueous layer wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.38 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.59 g, 56%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.3, 3H), 1.59-1.81 (m, 2H), 2.27(s, 3H), 2.50-2.67 (m, 2H), 3.79 (s, 2H), 5.23 (s, 2H), 7.08-7.75 (m,13H), 9.18 (s, 1H)

5-Benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   5-benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    sodium salt-   5-benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    potassium salt-   5-benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    0.5 calcium salt-   5-benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    hydrochloride-   5-benzyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one    hydrobromide

Example 2886-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-phenyl-2-propylpyrimidin-4(3H)-one

288a) 6-methyl-5-phenyl-2-propylpyrimidin-4(3H)-one

To a solution of ethyl 3-oxo-2-phenylbutanoate (2.28 g) andbutanimidamide hydrochloride (2.04 g) in N,N-dimethylformamide (30 mL)was added 1,8-diazabicyclo[5.4.0]undec-7-ene (5.0 mL), and the mixturewas stirred at 100° C. for 15 hr. Ethyl acetate and water were added tothe reaction mixture, and the aqueous layer was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow viscous substance (0.26 g, 10%).

¹H NMR (300 MHz, CDCl₃) δ 0.72-1.20 (m, 3H), 1.71-1.86 (m, 2H), 2.22 (s,3H), 2.52-2.63 (m, 2H), 7.27-7.48 (m, 5H), 12.06 (s, 1H)

288b)4′-[(4-methyl-6-oxo-5-phenyl-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of 6-methyl-5-phenyl-2-propylpyrimidin-4(3H)-one (0.26 g)and 4′-(bromomethyl)biphenyl-2-carbonitrile (0.37 g) inN,N-dimethylformamide (6 mL) was added 60% sodium hydride (0.06 g), andthe mixture was stirred at room temperature for 3 hr. Ethyl acetate andwater were added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (0.30 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.3, 3H), 1.65-1.93 (m, 2H), 2.23(s, 3H), 2.63-2.81 (m, 2H), 5.39 (br s, 2H), 7.27-7.85 (m, 13H)

288c)6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-phenyl-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.39 g), sodium hydrogencarbonate (0.59 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,4′-[(4-methyl-6-oxo-5-phenyl-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.30 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.14g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.19 g, 55%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.3, 3H), 1.71-1.86 (m, 2H), 2.17(s, 3H), 2.66-2.77 (m, 2H), 5.25 (s, 2H), 7.17-7.74 (m, 13H), 8.75 (s,1H)

Example 289

ethyl[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]acetate

A mixture of hydroxylammonium chloride (1.20 g), sodium hydrogencarbonate (1.90 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min, ethyl[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]acetate(0.50 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.29 g,51%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.5), 1.29 (3H, t, J=7.2),1.34-1.48 (2H, m), 1.58-1.74 (2H, m), 2.45 (3H, s), 2.56-2.68 (2H, m),3.92 (2H, s), 4.24 (2H, q, J=7.2), 4.74 (2H, s), 7.18-7.32 (4H, m),7.36-7.42 (1H, m), 7.44-7.51 (1H, m), 7.55-7.62 (1H, m), 7.84-7.90 (1H,m)

Example 290

[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]aceticacid

A mixture of ethyl[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]acetate(0.25 g), 1 M aqueous sodium hydroxide solution (1.2 mL),tetrahydrofuran (3 mL) and ethanol (3 mL) was stirred at roomtemperature for 3 hr. 1 M hydrochloric acid (1.2 mL) was added to thereaction solution, and the mixture was stirred for 10 min. The reactionmixture was diluted with ethyl acetate, washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to give the title compound as colorless crystals (0.22g, 92%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.5), 1.34-1.48 (2H, m),1.58-1.74 (2H, m), 2.50 (3H, s), 2.64-2.72 (2H, m), 3.83 (2H, s), 4.56(2H, s), 7.15-7.28 (4H, m), 7.44-7.52 (2H, m), 7.58-7.66 (1H, m),7.79-7.85 (1H, m)

Example 291

6-butyl-2-methyl-3-(2-morpholin-4-yl-2-oxoethyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]aceticacid (0.12 g), morpholine (0.033 g), 1-hydroxybenzotriazole (0.035 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.05 g) andN,N-dimethylformamide (3 mL) was stirred at room temperature for 15 hr.The reaction mixture was diluted with ethyl acetate, washed with dilutedhydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.080g, 59%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.5), 1.36-1.52 (2H, m),1.56-1.70 (2H, m), 2.63 (3H, s), 2.66-2.76 (2H, m), 3.54-3.80 (8H, m),3.89 (2H, s), 4.88 (2H, s), 7.17-7.28 (4H, m), 7.37-7.52 (2H, m),7.55-7.63 (1H, m), 7.75-7.82 (1H, m)

Example 292

N-(tert-butyl)-2-[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]acetamide

A mixture of[4-butyl-2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-1(6H)-yl]aceticacid (0.10 g), tert-butylamine (0.02 g), 1-hydroxybenzotriazole (0.03g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.044g) and N,N-dimethylformamide (3 mL) was stirred at room temperature for15 hr. The reaction mixture was diluted with ethyl acetate, washed withdiluted hydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.074g, 66%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.5), 1.33 (9H, s), 1.36-1.48(2H, m), 1.52-1.70 (2H, m), 2.66-2.76 (5H, m), 3.88 (2H, s), 4.58 (2H,s), 6.37 (1H, s), 7.14-7.26 (4H, m), 7.36-7.52 (2H, m), 7.55-7.63 (1H,m), 7.75-7.80 (1H, m)

Example 2933-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

293a)4′-({1-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({1-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.70 g) in N,N-dimethylformamide (7 mL) were added 60% sodium hydride(0.07 g) and then methyl iodide (0.18 mL) at 0° C., and the mixture wasstirred for 1 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (0.53 g, 74%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.33 (d, J=6.4, 3H),1.61-1.78 (m, 2H), 2.17 (s, 3H), 2.59-2.71 (m, 2H), 3.42 (s, 3H),3.46-3.65 (m, 2H), 3.97 (s, 2H), 4.50-4.63 (m, 1H), 7.01-7.78 (m, 12H)

293b)3-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.88 g), sodium hydrogencarbonate (1.32 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.52 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.22g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.36 g, 41%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.25 (d, J=6.2, 3H),1.46-1.61 (m, 2H), 2.07 (s, 3H), 2.47-2.53 (m, 2H), 3.30 (s, 3H),3.42-3.56 (m, 2H), 3.86 (s, 2H), 4.62-4.74 (m, 1H), 7.02-7.73 (m, 12H),12.38 (s, 1H)

3-[4-(2-Methoxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt-   3-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    potassium salt-   3-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    0.5 calcium salt-   3-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrochloride-   3-[4-(2-methoxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    hydrobromide

Example 294

3,6-dibutyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min, 1-iodobutane (0.64 mL) wasadded, and the mixture was stirred at room temperature for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue obtained by silica gel columnchromatography was dissolved in dimethyl sulfoxide (5 mL) and added to amixture of hydroxylammonium chloride (1.27 g), sodium hydrogen carbonate(2.05 g) and dimethyl sulfoxide (10 mL), which had been mixed at 40° C.for 30 min. The reaction mixture was stirred at 90° C. for 16 hr,diluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was dissolved intetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.24 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.24 g,42%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.3), 0.92 (3H, t, J=7.3),1.18-1.48 (6H, m), 1.51-1.66 (2H, m), 2.41-2.50 (5H, m), 3.84 (2H, s),3.88-4.00 (2H, m), 7.13-7.30 (4H, m), 7.44-7.59 (2H, m), 7.63-7.72 (2H,m), 12.38 (1H, s)

3,6-Dibutyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-oneobtained above is subjected to a conventional method of salt formationto give the following salts.

-   3,6-dibutyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    sodium salt-   3,6-dibutyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    potassium salt-   3,6-dibutyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    0.5 calcium salt-   3,6-dibutyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrochloride-   3,6-dibutyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one    hydrobromide

Example 2956-butyl-3-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

295a)4′-{[4-butyl-1-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a mixture of cyclohexanecarbaldehyde (1.6 g), diiodomethane (1.39 mL)and tetrahydrofuran (40 mL) was added methyllithium (2.1 M diethyl ethersolution, 13.9 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 4 hr, and extracted with saturated aqueous ammoniumchloride solution and diethyl ether. The diethyl ether layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The obtained oil wasdissolved in N,N-dimethylformamide (15 mL),4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.0 g) and potassium carbonate (1.5 g) were added, and the mixture wasstirred at 90° C. for 24 hr. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (1.75 g, 65%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.3), 1.10-1.92 (14H, m),2.52-2.63 (5H, m), 3.07 (1H, d, J=4.9), 3.71-3.83 (1H, m), 3.92-4.09(3H, m), 4.13-4.27 (1H, m), 7.29-7.52 (6H, m), 7.58-7.66 (1H, m), 7.74(1H, d, J=7.7)

295b)6-butyl-3-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (3.80 g), sodium hydrogencarbonate (6.08 g) and dimethyl sulfoxide (30 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.75 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (40 mL). N,N′-carbonyldiimidazole (0.7 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.51 g,26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.2), 1.09-1.52 (10H, m),1.55-1.88 (5H, m), 2.41-2.47 (2H, m), 2.53 (3H, s), 3.50-3.70 (2H, m),3.84 (2H, dd, J=23.6, 15.3), 4.18 (1H, d, J=11.9), 4.91 (1H, d, J=5.5),7.17-7.30 (4H, m), 7.41-7.60 (2H, m), 7.60-7.76 (2H, m), 12.38 (1H, s)

Example 296

6-butyl-3-(2-cyclohexyl-2-oxoethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of6-butyl-3-(2-cyclohexyl-2-hydroxyethyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.3 g), 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.35 g) and methylene chloride (15 mL) was stirred at room temperaturefor 2 hr. Saturated aqueous sodium hydrogen carbonate solution andsodium thiosulfate were added to the reaction mixture, and the mixturewas stirred at room temperature for 2 hr and extracted with chloroform.The chloroform layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The obtained residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.22 g,74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.3), 1.13-1.37 (7H, m),1.35-1.55 (2H, m), 1.58-1.78 (3H, m), 1.83-1.97 (2H, m), 2.27 (3H, s),2.42-2.49 (2H, m), 2.57-2.71 (1H, m), 3.83 (2H, s), 5.07 (2H, s), 7.20(4H, s), 7.42-7.60 (2H, m), 7.62-7.75 (2H, m), 12.38 (1H, s)

Example 2976-butyl-3-(2-hydroxy-2-methylpropyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

297a)4′-{[4-butyl-1-(2-hydroxy-2-methylpropyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), 2,2-dimethyloxirane (2.5 mL), cesium carbonate (1.83 g) andN,N-dimethylacetamide (10 mL) was stirred at 100° C. for 24 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.92 g,76%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.3), 1.29 (6H, s), 1.32-1.44(2H, m), 1.50-1.60 (2H, m), 2.53-2.65 (5H, m), 3.97 (2H, s), 4.17 (2H,s), 4.35 (1H, s), 7.30-7.37 (2H, m), 7.37-7.51 (4H, m), 7.57-7.67 (1H,m), 7.74 (1H, dd, J=7.7, 0.9)

297b)6-butyl-3-(2-hydroxy-2-methylpropyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.23 g), sodium hydrogencarbonate (3.60 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[4-butyl-1-(2-hydroxy-2-methylpropyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.92 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.42 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.25 g,24%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (3H, t, J=7.4), 1.13 (6H, s), 1.20-1.35(2H, m), 1.38-1.50 (2H, m), 2.40-2.48 (2H, m), 2.61 (3H, s), 3.85 (2H,s), 4.05 (2H, br), 4.83 (1H, s), 7.13-7.27 (4H, m), 7.44-7.58 (2H, m),7.60-7.75 (2H, m), 12.37 (1H, s)

Example 2983-{[5-(hydroxymethyl)pyridin-2-yl]methyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

298a) 2-bromo-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine

To a mixture of 6-bromonicotinaldehyde (10 g) and methanol (100 mL) wasadded sodium borohydride (2.44 g) at 0° C., and the reaction mixture wasstirred at room temperature for 2 hr. The solvent was evaporated underreduced pressure, and the obtained residue was extracted with saturatedaqueous ammonium chloride solution and ethyl acetate. The ethyl acetatelayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The obtained residue was dissolved in dichloromethane (50 mL),tert-butyldimethylsilylchloride (8.92 g), triethylamine (8.25 mL) and4-dimethylaminopyridine (0.33 g) were added, and the mixture was stirredat room temperature for 2 hr. The reaction mixture was washed with waterand then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless oil (11 g, 64%).

¹H NMR (300 MHz, CDCl₃) δ 0.11 (6H, s), 0.93 (9H, s), 4.71 (2H, s),7.42-7.58 (2H, m), 8.32 (1H, s)

298b) [5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]methanol

To a mixture of2-bromo-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridine (11 g) andtetrahydrofuran (450 mL) was added n-butyllithium (1.6 M hexanesolution, 25.3 mL) at −78° C., and the reaction mixture was stirred for1 hr. Then, N,N-dimethylformamide (3.17 mL) was added at −78° C., andthe temperature of the mixture was raised to room temperature andstirred for 16 hr. The reaction mixture was diluted with diethyl ether,washed with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The obtained residuewas dissolved in methanol (200 mL), sodium borohydride (1.95 g) wasadded at 0° C., and the reaction mixture was stirred at room temperaturefor 2 hr. The solvent was evaporated under reduced pressure, and theobtained residue was extracted with saturated aqueous ammonium chloridesolution and ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (7.53 g, 64%).

¹H NMR (300 MHz, CDCl₃) δ 0.11 (6H, s), 0.92 (9H, s), 4.75 (4H, s),7.15-7.37 (1H, m), 7.50-7.77 (1H, m), 8.50 (1H, s)

298c)4′-[(1-{[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]methyl}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.6 g), 1,1′-(azodicarbonyl)dipiperidine (0.48 g), tributylphosphine(0.95 g),[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]methanol (0.48g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr.The reaction mixture was concentrated, and the residue was diluted withethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.54 g,49%).

¹H NMR (300 MHz, CDCl₃) δ 0.09 (6H, s), 0.89-1.01 (12H, m), 1.54-1.70(2H, m), 2.52-2.63 (5H, m), 3.98 (2H, s), 4.73 (2H, s), 5.36 (2H, s),7.21-7.28 (1H, m), 7.34-7.50 (6H, m), 7.59-7.66 (2H, m), 7.74 (1H, d,J=6.8), 8.48 (1H, s)

298d)3-{[5-(hydroxymethyl)pyridin-2-yl]methyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogencarbonate (1.56 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-[(1-{[5-({[tert-butyl(dimethyl)silyl]oxy}methyl)pyridin-2-yl]methyl}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.18 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was adjusted to pH 5 with water and 1 M hydrochloric acid, andextracted with ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (20 mL), tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 2.7 mL) was added, and the mixture was stirredat room temperature for 3 hr. The reaction mixture was adjusted to pH 5with water and 1 M hydrochloric acid, and extracted with ethyl acetate.The ethyl acetate layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.27 g,56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.4), 1.43-1.62 (2H, m),2.43-2.51 (5H, m), 3.85 (2H, s), 4.49 (2H, s), 5.24-5.36 (3H, m),7.14-7.27 (4H, m), 7.30 (1H, d, J=8.0), 7.44-7.56 (2H, m), 7.60-7.77(3H, m), 8.41 (1H, s), 12.37 (1H, s)

Example 2993-(2,3-dihydro-1-benzofuran-5-yl)-6-ethoxy-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

299a) diethyl [(2′-cyanobiphenyl-4-yl)methyl]malonate

To a mixture of sodium hydride (2.86 g) and tetrahydrofuran (250 mL)were added a solution of diethyl malonate (16.7 mL) in tetrahydrofuran(100 mL) and then 4′-(bromomethyl)biphenyl-2-carbonitrile (15 g), andthe mixture was stirred at room temperature for 16 hr. The reactionmixture was concentrated under reduced pressure, and the obtainedresidue was extracted with 5% aqueous potassium hydrogen sulfatesolution and ethyl acetate. The ethyl acetate layer was washed withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless oil (18.3 g, 95%).

¹H NMR (300 MHz, CDCl₃) δ 1.23 (6H, t, J=7.2), 3.28 (2H, d, J=7.6), 3.70(1H, s), 4.18 (4H, q, J=7.2), 7.34 (2H, d, J=8.3), 7.41-7.54 (4H, m),7.63 (1H, s), 7.75 (1H, d, J=7.6)

299b)4′-[(4-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a solution of acetamidine hydrochloride (2.68 g) in ethanol (30 mL)were added sodium ethoxide (20% ethanol solution, 14.5 g) and then asolution of diethyl [(2′-cyanobiphenyl-4-yl)methyl]malonate in ethanol(30 mL)-1,4-dioxane (15 mL) at 0° C., and the reaction mixture wasstirred at room temperature for 16 hr. The reaction mixture wasconcentrated, and the residue was adjusted to pH 5 with water (50 mL)and 50% aqueous acetic acid solution. The obtained crystallized productwas collected by filtration and washed with water to give the titlecompound as colorless crystals (1.8 g, 40%).

¹H NMR (300 MHz, DMSO-d₆) δ 2.23 (3H, s), 3.62 (2H, s), 7.27-7.49 (4H,m), 7.48-7.63 (2H, m), 7.77 (1H, t, J=7.6), 7.92 (1H, d, J=7.6),11.56-12.08 (2H, m)

299c)4′-[(4-ethoxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(4-hydroxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1 g), cesium carbonate (3.01 g), diethyl sulfate (0.41 mL) andN,N-dimethylformamide (20 mL) was stirred at 0° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with 5% aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.17 g,16%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.25 (3H, t, J=7.0), 2.27 (3H, s), 3.67 (2H,s), 4.31 (2H, q, J=7.2), 7.35 (2H, d, J=8.0), 7.39-7.49 (2H, m),7.48-7.60 (2H, m), 7.72-7.81 (1H, m), 7.92 (1H, d, J=7.6), 12.35 (1H, s)

299d)4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-4-ethoxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-ethoxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.17 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (0.16 g),triethylamine (0.17 mL), pyridine (0.34 mL) and molecular sieves 4 A(0.34 g) in tetrahydrofuran (5 mL) was added copper(II) acetate (0.17g), and the mixture was stirred for 1 day. The reaction mixture wasdiluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.21 g, 92%).

¹H NMR (300 MHz, CDCl₃) δ 1.41 (3H, t, J=7.0), 2.17 (3H, s), 3.16-3.35(2H, m), 3.84 (2H, s), 4.44 (2H, q, J=6.9), 4.63 (2H, t, J=8.9),6.82-6.95 (2H, m), 7.01 (1H, s), 7.35-7.65 (7H, m), 7.74 (1H, d, J=8.0)

299e)3-(2,3-dihydro-1-benzofuran-5-yl)-6-ethoxy-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.47 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[1-(2,3-dihydro-1-benzofuran-5-yl)-4-ethoxy-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.21 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.088 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.074 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.083g, 35%).

¹H NMR (300 MHz, DMSO-d₆) δ 1.29 (3H, t, J=7.1), 2.10 (3H, s), 3.22 (2H,t, J=8.7), 3.68 (2H, s), 4.37 (2H, q, J=7.0), 4.61 (2H, t, J=8.9), 6.86(1H, d, J=8.5), 7.03 (1H, dd, J=8.5, 2.3), 7.17-7.24 (3H, m), 7.26-7.33(2H, m), 7.47-7.58 (2H, m), 7.61-7.71 (2H, m), 12.39 (1H, s)

Example 3005-(2,3-difluorobenzyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

300a) ethyl 2-(2,3-difluorobenzyl)-3-oxobutyrate

A solution of 1-(bromomethyl)-2,3-difluorobenzene (1.6 g) and ethylacetoacetate sodium salt (2.36 g) in tetrahydrofuran (20 mL) was stirredfor 12 hr. The insoluble material was filtered off, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound (1.56 g, 79%) as a colorlessviscous oil.

¹H NMR (300 MHz, CDCl₃) δ 1.29 (3H, t, J=7.2), 2.28 (3H, s), 3.21 (1H,t, J=7.2), 4.09-4.25 (4H, m), 6.90-7.13 (3H, m)

300b) 5-(2,3-difluorobenzyl)-6-methyl-2-propylpyrimidin-4(3H)-one

To a solution of ethyl 2-(2,3-difluorobenzyl)-3-oxobutyrate (1.56 g) andpropylamidine hydrochloride (1.5 g) in methanol (10 mL) was added sodiummethoxide (28% methanol solution, 3.53 mL), and the mixture was stirredfor 12 hr. The reaction mixture was concentrated, and the residue wasdissolved in water and diethyl ether. The aqueous layer was separatedand weakly acidified with 1 M hydrochloric acid. The precipitate wascollected by filtration and dried under reduced pressure to give thetitle compound (0.55 g, 22%) as colorless crystals.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.4), 1.59-1.73 (2H, m), 2.15(3H, s), 2.40-2.48 (2H, m), 3.79 (2H, s), 6.89 (1H, t, J=7.2), 7.01-7.13(1H, m), 7.17-7.33 (1H, m), 12.32 (1H, br)

300c)5-(2,3-difluorobenzyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

To a solution of5-(2,3-difluorobenzyl)-6-methyl-2-propylpyrimidin-4(3H)-one (0.55 g) and3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole(1.03 g) in N,N-dimethylformamide (5 mL) was added cesium carbonate(0.44 g), and the mixture was stirred for 12 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andsaturated brine and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved in acetone(10 mL), 1 M sodium hydroxide (2 mL) was added, and the mixture wasstirred for 30 min. The reaction mixture was weakly acidified with 1 Mhydrochloric acid, and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography to give the title compound(0.11 g, 20%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.4), 1.47-1.70 (2H, m), 2.25(3H, s), 2.62 (2H, t, J=7.4), 3.90 (2H, s), 5.33 (2H, s), 6.94 (1H, t,J=7.0), 7.02-7.40 (6H, m), 7.55 (2H, dd, J=17.4, 7.6), 7.63-7.77 (2H,m), 12.40 (1H, s)

Example 301

3-[4′-({3-butyl-1-[2-(4-methoxyphenyl)-2-oxoethyl]-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl}methyl)biphenyl-2-yl]-1,2,4-oxadiazol-5(4H)-one

A mixture of4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(0.6 g), sodium hydride (0.11 g) and N,N-dimethylformamide (10 mL) wasstirred at room temperature for 10 min,2-bromo-1-(4-methoxyphenyl)ethanone (0.54 g) was added, and the mixturewas stirred at room temperature for 16 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue obtained by silica gel column chromatography was dissolvedin dimethyl sulfoxide (5 mL) and added to a mixture of hydroxylammoniumchloride (0.83 g), sodium hydrogen carbonate (1.25 g) and dimethylsulfoxide (20 mL), which had been mixed at 40° C. for 30 min. Thereaction mixture was stirred at 90° C. for 16 hr, diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was dissolved in tetrahydrofuran (20 mL).N,N′-carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.029 g,3%).

¹H NMR (300 MHz, CDCl₃) δ 0.86 (3H, t, J=7.3), 1.27-1.41 (2H, m),1.51-1.66 (2H, m), 2.37-2.48 (2H, m), 3.88 (3H, s), 4.84 (2H, s), 5.16(2H, s), 6.95 (2H, d, J=9.0), 7.24-7.36 (4H, m), 7.36-7.49 (2H, m),7.53-7.61 (1H, m), 7.71 (1H, d, J=7.7), 7.91 (2H, d, J=8.9)

Example 3023-(4′-{[3-butyl-1-(3,3-dimethyl-2-oxobutyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

302a)4′-{[3-butyl-1-(3,3-dimethyl-2-oxobutyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(3-butyl-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)methyl]biphenyl-2-carbonitrile(0.7 g), potassium tert-butoxide (1.0 M tetrahydrofuran solution, 1.75mL) and N,N-dimethylformamide (10 mL) was stirred at room temperaturefor 10 min, 1-bromo-3,3-dimethylbutan-2-one (0.22 mL) was added, and themixture was stirred at room temperature for 16 hr. The reaction mixturewas diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless powder (0.58 g,92%).

¹H NMR (300 MHz, CDCl₃) δ 0.86 (3H, t, J=7.3), 1.26 (9H, s), 1.27-1.40(2H, m), 1.50-1.60 (1H, m), 2.39-2.46 (2H, m), 4.81 (2H, s), 4.91 (2H,s), 7.34-7.51 (4H, m), 7.53-7.59 (2H, m), 7.61-7.69 (1H, m), 7.77 (1H,dd, J=7.7, 0.9)

302b)3-(4′-{[3-butyl-1-(3,3-dimethyl-2-oxobutyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-yl)-1,2,4-oxadiazol-5(4H)-one

A mixture of hydroxylammonium chloride (1.12 g), sodium hydrogencarbonate (1.69 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[3-butyl-1-(3,3-dimethyl-2-oxobutyl)-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl]methyl}biphenyl-2-carbonitrile(0.58 g) was added, and the mixture was stirred at 90° C. for 16 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.42 g,63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.79 (3H, t, J=7.3), 1.16 (9H, s), 1.20-1.31(2H, m), 1.37-1.51 (2H, m), 2.42 (2H, t, J=7.4), 4.85 (2H, s), 4.90 (2H,s), 7.24-7.35 (4H, m), 7.49-7.62 (2H, m), 7.64-7.76 (2H, m), 12.41 (1H,s)

Example 303

2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-onepotassium salt

To a solution of2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.10 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.022 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.09 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.2), 1.24-1.40 (2H, m),1.53-1.68 (2H, m), 2.12 (3H, s), 2.70 (2H, t, J=7.2), 3.20 (2H, t,J=8.7), 4.55 (2H, t, J=8.7), 5.30 (2H, s), 6.78 (1H, d, J=8.1), 7.01(1H, d, J=8.1), 7.12 (2H, d, J=8.4), 7.18 (1H, s), 7.30 (3H, d, J=8.1),7.33-7.47 (2H, m), 7.51 (1H, d, J=5.7)

Example 304

2-butyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-fluorophenyl)-6-methylpyrimidin-4(3H)-onepotassium salt

To a solution of2-butyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-fluorophenyl)-6-methylpyrimidin-4(3H)-one(0.41 g) in ethanol (5 mL) was added 8 M potassium hydroxide solution(0.098 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.42 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.5), 1.24-1.43 (2H, m),1.55-1.72 (2H, m), 2.12 (3H, s), 2.73 (2H, t, J=7.5), 5.32 (2H, s),6.89-7.00 (1H, m), 7.06-7.48 (9H, m), 7.49-7.58 (1H, m)

Example 305

2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methylpyrimidin-4(3H)-onepotassium salt

To a solution of2-butyl-5-(2,3-dihydro-1-benzofuran-5-yl)-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methylpyrimidin-4(3H)-one(0.38 g) in ethanol (5 mL) was added 8 M potassium hydroxide solution(0.086 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.25 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.5), 1.26-1.41 (2H, m),1.55-1.71 (2H, m), 2.13 (3H, s), 2.71 (2H, t, J=7.5), 3.19 (2H, t,J=8.4), 4.54 (2H, t, J=8.4), 5.31 (2H, s), 6.77 (1H, d, J=8.4),6.87-7.03 (2H, m), 7.07-7.19 (3H, m), 7.28-7.35 (1H, m), 7.35-7.48 (2H,m), 7.53 (1H, d, J=9.0)

Example 306

6-butyl-3-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-onehydrochloride

To a mixture of6-butyl-3-[(1,5-dimethyl-1H-pyrazol-3-yl)methyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.25 g) and ethyl acetate (10 mL) was added 4 M hydrochloric acid-ethylacetate (0.14 mL) at room temperature. The obtained crystallized productwas collected by filtration to give the title compound as colorlesscrystals (0.18 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.2), 1.27-1.39 (2H, m),1.44-1.55 (2H, m), 2.07 (3H, s), 2.61-2.72 (2H, m), 2.75 (3H, s), 3.78(3H, s), 3.91 (2H, s), 5.29 (2H, s), 5.91 (1H, s), 7.17-7.32 (4H, m),7.45-7.61 (2H, m), 7.62-7.78 (2H, m), 12.48 (1H, s)

Example 307

6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyrazin-2-ylmethyl)pyrimidin-4(3H)-onehydrochloride

To a mixture of6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(pyrazin-2-ylmethyl)pyrimidin-4(3H)-one(0.4 g) and ethyl acetate (10 mL) was added 4 M hydrochloric acid-ethylacetate (0.22 mL) at room temperature. The obtained crystallized productwas collected by filtration to give the title compound as colorlesscrystals (0.37 g, 86%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.3), 1.25-1.41 (2H, m),1.41-1.58 (2H, m), 2.62-2.90 (5H, m), 3.88 (2H, s), 5.49 (2H, s), 7.22(4H, s), 7.45-7.60 (2H, m), 7.63-7.72 (2H, m), 8.53-8.62 (2H, m), 8.84(1H, d, J=3.2), 12.48 (1H, s)

Example 308

2-methyl-3-[(1-methyl-1H-indazol-3-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onehydrochloride

To a mixture of2-methyl-3-[(1-methyl-1H-indazol-3-yl)methyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.38 g) and ethyl acetate (10 mL) was added 4 M hydrochloric acid-ethylacetate (0.19 mL) at room temperature. The obtained crystallized productwas collected by filtration to give the title compound as colorlesscrystals (0.33 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.4), 1.37-1.60 (2H, m),2.55-2.69 (2H, m), 2.84 (3H, s), 3.92 (2H, s), 3.95-4.05 (3H, m), 5.62(2H, s), 7.06-7.17 (1H, m), 7.24 (4H, q, J=8.3), 7.36-7.46 (1H, m),7.47-7.75 (5H, m), 7.84 (1H, d, J=8.3), 12.44 (1H, s)

Example 309

6-butyl-3-(3,3-dimethyl-2-oxobutyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-onepotassium salt

6-Butyl-3-(3,3-dimethyl-2-oxobutyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(2.9 g) was dissolved in ethanol (30 mL), 8 M potassium hydroxidesolution (0.68 mL) was added, and the mixture was stirred for 3 days.The solvent was removed under reduced pressure, diethyl ether and hexanewere added, and the precipitated solid was collected by filtration togive the title compound (2.4 g, 76%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.1), 1.14 (3H, t, J=7.1),1.21 (9H, s), 1.23-1.39 (2H, m), 1.47-1.60 (2H, m), 2.47-2.59 (4H, m),3.79 (2H, s), 5.14 (2H, s), 7.05-7.09 (2H, m), 7.16-7.22 (2H, m),7.25-7.48 (4H, m)

Example 310

6-butyl-2-cyclopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-onepotassium salt

6-Butyl-2-cyclopropyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-phenylpyrimidin-4(3H)-one(0.52 g) was dissolved in ethanol (5 mL), 8 M potassium hydroxidesolution (0.13 mL) was added, and the mixture was stirred for 1 hr.Diethyl ether and diisopropyl ether were added to the reaction mixture,and the precipitated solid was collected by filtration to give the titlecompound (0.46 g, 83%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.75-0.82 (2H, m), 0.86 (3H, t, J=7.2),0.96-1.13 (2H, m), 1.22-1.40 (3H, m), 1.45-1.53 (2H, m), 2.45-2.56 (2H,m), 3.80 (2H, s), 7.08-7.63 (13H, m)

Example 311

3-(2,3-dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

3-(2,3-Dihydro-1-benzofuran-5-yl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(2.2 g) was dissolved in ethanol (21 mL), 8 M potassium hydroxidesolution (0.50 mL) was added, and the mixture was stirred overnight.Diethyl ether and diisopropyl ether were added to the reaction mixture,and the precipitated solid was collected by filtration to give the titlecompound (2.1 g, 92%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.3), 1.05 (3H, t, J=7.0),1.54-1.71 (2H, m), 2.30 (2H, q, J=7.1), 2.48-2.61 (2H, m), 3.23 (2H, t,J=8.6), 3.82 (2H, s), 4.60 (2H, t, J=8.6), 6.85 (1H, d, J=8.2), 7.05(1H, dd, J=8.2, 2.0), 7.11-7.50 (9H, m)

Example 312

2-ethyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

2-Ethyl-3-(2-methyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(2.3 g) was dissolved in ethanol (22 mL), 8 M potassium hydroxidesolution (0.51 mL) was added, and the mixture was stirred overnight.Diethyl ether and diisopropyl ether were added to the reaction mixture,and the precipitated solid was collected by filtration to give the titlecompound (2.3 g, 94%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.3), 1.02-1.12 (3H, m),1.38-1.46 (3H, m), 1.55-1.70 (2H, m), 2.24-2.36 (2H, m), 2.47-2.60 (2H,m), 2.76-2.89 (1H, m), 3.30-3.50 (1H, m), 3.81 (2H, s), 4.92-5.06 (1H,m), 6.82 (1H, d, J=8.4), 7.04 (1H, dd, J=8.4, 1.8), 7.11-7.51 (9H, m)

Example 313

2-ethyl-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

2-Ethyl-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(2.2 g) was dissolved in ethanol (22 mL), 8 M potassium hydroxidesolution (0.53 mL) was added, and the mixture was stirred for 1 hr. Themixture was concentrated under reduced pressure, and acetone and hexanewere added to the residue. The precipitated solid was collected byfiltration to give the title compound (2.3 g, 95%) as an amorphoussolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.3), 1.00-1.13 (6H, m),1.55-1.70 (2H, m), 2.27 (2H, q, J=7.2), 2.48-2.63 (2H, m), 3.38-3.52(2H, m), 6.99-7.53 (12H, m)

Example 314

3-(4-fluorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

3-(4-Fluorophenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.4 g) was dissolved in ethanol (10 mL), 8 M potassium hydroxidesolution (0.51 mL) was added, and the mixture was stirred overnight.Ethyl acetate and diisopropyl ether were added to the reaction mixture.The precipitated solid was collected by filtration to give the titlecompound (0.35 g, 81%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.88-0.98 (3H, m), 1.48-1.68 (2H, m), 2.05(3H, s), 2.46-2.57 (2H, m), 3.82 (2H, s), 7.10-7.54 (12H, m)

Example 315

6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-onepotassium salt

To a solution of6-butyl-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.42 g) in ethanol (4 mL) was added 8 M potassium hydroxide solution(0.093 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.42 g, 94%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87 (t, J=7.2, 3H), 1.20-1.64 (m, 10H),2.07 (s, 3H), 2.49-2.62 (m, 2H), 3.05 (s, 2H), 3.80 (s, 2H), 6.60-7.62(m, 11H)

Example 316

316a)3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(2.8 g) in ethanol (15 mL) was added 8 M potassium hydroxide solution(0.65 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (2.9 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.44 (s, 3H), 1.45 (s,3H), 1.50-1.66 (m, 2H), 2.07 (s, 3H), 2.51-2.58 (m, 2H), 3.05 (s, 2H),3.80 (s, 2H), 6.73-7.53 (m, 11H)

316b) Crystalline3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a suspension of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(45 g) in acetone (135 ml) was added 8 M aqueous potassium hydroxidesolution (10.3 mL) and the mixture was stirred at room temperature for20 hr. The obtained precipitate was collected, washed with acetone andwater successively, and dried under reduced pressure at 80° C. for 5 hrto give the title compound (32 g, 60%) as colorless crystals.

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.44 (s, 3H), 1.45 (s,3H), 1.51-1.66 (m, 2H), 2.07 (s, 3H), 2.48-2.57 (m, 2H), 3.05 (s, 2H),3.81 (s, 2H), 6.74-7.51 (m, 11H)

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):5.02, 5.36, 9.46, 10.66, 11.80, 13.42, 17.06, 17.78, 19.00, 19.18,20.18, 20.88, 21.38, 23.26, 23.78, 25.06, 25.74, 26.06, 26.90, 27.34.

Anal calcd for C₃₃H₃₁N₄O₄K+2.9H₂O: C, 62.03; H, 5.81; N, 8.77.

Found C, 62.09; H, 5.75; N, 8.73.

Example 317

6-butyl-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[(2Z)-2-(isopropoxyimino)-3,3-dimethylbutyl]-2-methylpyrimidin-4(3H)-one

A mixture of6-butyl-3-(3,3-dimethyl-2-oxobutyl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methylpyrimidin-4(3H)-one(0.15 g), 2-(aminooxy)propane hydrochloride (0.63 g) and pyridine (5 mL)was stirred at 100° C. for 16 hr. The mixture was allowed to cool toroom temperature, and the reaction mixture was diluted with ethylacetate, washed with 1 M hydrochloric acid and then with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound as a colorlessamorphous solid (0.036 g, 22%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.4), 0.88 (6H, d, J=6.2),1.15 (9H, s), 1.20-1.31 (2H, m), 1.36-1.51 (2H, m), 2.39-2.48 (5H, m),3.81 (2H, s), 3.90-4.02 (1H, m), 4.81 (2H, s), 6.95 (1H, dd, J=7.9,1.7), 7.06 (1H, t, J=8.0), 7.15 (1H, dd, J=11.1, 1.7), 7.48-7.61 (2H,m), 7.63-7.74 (2H, m), 12.45 (1H, br)

Example 3183-[4-(cyclobutyloxy)-3-fluorophenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

318a)4′-({1-[4-(cyclobutyloxy)-3-fluorophenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(3-fluoro-4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and bromocyclobutane (0.90 g) in N,N-dimethylformamide (10 mL)was added cesium carbonate (1.44 g), and the mixture was stirred at 80°C. for 15 hr. After allowing to cool, ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (0.96 g, 86%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.60-1.98 (m, 4H),2.14-2.56 (m, 7H), 2.60-2.70 (m, 2H), 3.96 (s, 2H), 4.61-4.79 (m, 1H),6.87-7.82 (m, 11H)

318b)3-[4-(cyclobutyloxy)-3-fluorophenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.58 g), sodium hydrogencarbonate (2.39 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(cyclobutyloxy)-3-fluorophenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.96 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.37g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.56 g, 52%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.43-2.24 (m, 9H),2.40-2.55 (m, 4H), 3.86 (s, 2H), 4.72-4.91 (m, 1H), 7.08-7.74 (m, 11H),12.38 (s, 1H)

Example 3193-[4-(cyclopentyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

319a)4′-({1-[4-(cyclopentyloxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and bromocyclopentane (1.00 g) in N,N-dimethylformamide (10 mL)was added cesium carbonate (1.44 g), and the mixture was stirred at 80°C. for 15 hr. After allowing to cool, ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (1.05 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.53-1.99 (m, 10H), 2.18(s, 3H), 2.58-2.73 (m, 2H), 3.97 (s, 2H), 4.73-4.82 (m, 1H), 6.90-7.78(m, 12H)

319b)3-[4-(cyclopentyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogencarbonate (2.62 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(cyclopentyloxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.96 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.41g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.78 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.44-2.01 (m, 10H),2.06 (s, 3H), 2.45-2.55 (m, 2H), 3.86 (s, 2H), 4.82-4.94 (m, 1H),6.98-7.73 (m, 12H), 12.37 (s, 1H)

Example 320

2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(tetrahydrofuran-3-yloxy)phenyl]pyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.00 g), tetrahydrofuran-3-ol (0.37 mL) and triphenylphosphine (1.21 g)in tetrahydrofuran (7 mL) was added diisopropyl azodicarboxylate (1.9 Mtoluene solution, 0.91 mL), and the mixture was stirred for 1 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was crudely purified by silica gel columnchromatography. This was added to a mixture of hydroxylammonium chloride(1.90 g), sodium hydrogen carbonate (2.90 g) and dimethyl sulfoxide (10mL), which had been stirred at 40° C. for 30 min, and the mixture wasstirred at 90° C. for 18 hr. The reaction mixture was allowed to cool toroom temperature, ethyl acetate and water were added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was dissolved in tetrahydrofuran (20 mL).N,N′-carbonyldiimidazole (0.45 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.69 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.43-1.65 (m, 2H),1.91-2.36 (m, 5H), 2.45-2.56 (m, 2H), 3.67-3.99 (m, 6H), 5.03-5.14 (m,1H), 7.00-7.74 (m, 12H), 12.38 (s, 1H)

Example 321

3-[4-(2-fluoro-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-[4-(2-fluoro-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.35 g) in ethanol (3 mL) was added 8 M potassium hydroxide solution(0.079 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a pale-yellow amorphous solid (0.38 g, 100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.27 (dd, J=6.4, 1.1,3H), 1.53-1.67 (m, 2H), 2.06 (s, 3H), 2.47-2.57 (m, 2H), 3.81 (s, 2H),4.40-4.92 (m, 3H), 7.04-7.51 (m, 12H)

Example 3223-(3-chloro-4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

322a)4′-{[1-(3-chloro-4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (3-chloro-4-isopropoxyphenyl)boronic acid (1.00 g),triethylamine (2.00 mL), pyridine (1.00 mL) and molecular sieves 4 A(2.0 g) in methylene chloride (15 mL) was added copper(II) acetate (1.00g), and the mixture was stirred for 2 days. The reaction mixture wasdiluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow viscous substance (1.00 g, 67%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.41 (dd, J=10.6, 6.1,6H), 1.60-1.78 (m, 2H), 2.19 (s, 3H), 2.58-2.71 (m, 2H), 3.96 (s, 2H),4.51-4.68 (m, 1H), 6.98-7.79 (m, 11H)

322b)3-(3-chloro-4-isopropoxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.63 g), sodium hydrogencarbonate (2.46 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(3-chloro-4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.00 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.41g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.39 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.63 g, 57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.3, 3H), 1.33 (dd, J=5.9, 3.3,6H), 1.44-1.61 (m, 2H), 2.09 (s, 3H), 2.45-2.53 (m, 2H), 3.86 (s, 2H),4.66-4.84 (m, 1H), 7.16-7.74 (m, 11H), 12.38 (s, 1H)

Example 3232-methyl-3-(2-methylprop-1-en-1-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

323a)4′-{[2-methyl-1-(2-methylprop-1-en-1-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (2-methylprop-1-en-1-yl)boronic acid (1.00 g), triethylamine(2.00 mL), pyridine (1.00 mL) and molecular sieves 4 A (2.0 g) inmethylene chloride (15 mL) was added copper(II) acetate (1.00 g), andthe mixture was stirred for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (0.080 g, 7%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.4, 3H), 1.49-1.73 (m, 8H), 2.34(s, 3H), 2.51-2.65 (m, 2H), 3.95 (s, 2H), 6.05 (s, 1H), 7.31-7.78 (m,8H)

323b)2-methyl-3-(2-methylprop-1-en-1-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.21 g), sodium hydrogencarbonate (0.34 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-1-(2-methylprop-1-en-1-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.080 g) was added, and the mixture was stirred at 90° C. for 18 hr.The reaction mixture was allowed to cool to room temperature, ethylacetate and water were added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was dissolved in tetrahydrofuran (2 mL).N,N′-carbonyldiimidazole (0.050 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.050 mL) were added, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.029 g, 32%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.3, 3H), 1.42 (d, J=0.9, 3H),1.45-1.58 (m, 2H), 1.84 (d, J=1.3, 3H), 2.27 (s, 3H), 2.42-2.52 (m, 2H),3.84 (s, 2H), 6.12 (s, 1H), 7.16-7.74 (m, 8H), 12.36 (s, 1H)

Example 324

2-methyl-3-{4-[(1-methylbut-3-yn-1-yl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.00 g), pent-4-yn-2-ol (0.43 mL) and triphenylphosphine (1.21 g) intetrahydrofuran (10 mL) was added diisopropyl azodicarboxylate (1.9 Mtoluene solution, 0.91 mL), and the mixture was stirred for 1 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was crudely purified by silica gel columnchromatography. This was added to a mixture of hydroxylammonium chloride(0.81 g), sodium hydrogen carbonate (1.31 g) and dimethyl sulfoxide (8mL), which had been stirred at 40° C. for 30 min, and the mixture wasstirred at 90° C. for 18 hr. The reaction mixture was allowed to cool toroom temperature, ethyl acetate and water were added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was dissolved in tetrahydrofuran (20 mL).N,N′-carbonyldiimidazole (0.15 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.077 g, 6%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.36 (d, J=6.0, 2H),1.47-1.61 (m, 2H), 2.07 (s, 3H), 2.49-2.59 (m, 2H), 2.91 (t, J=2.6, 1H),3.28-3.34 (m, 2H), 3.86 (s, 2H), 4.61-4.71 (m, 1H), 7.00-7.72 (m, 12H),12.38 (s, 1H)

Example 3253-(6-isopropoxypyridin-3-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

325a)4′-{[1-(6-isopropoxypyridin-3-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (6-isopropoxypyridin-3-yl)boronic acid (1.00 g), triethylamine(2.00 mL), pyridine (1.00 mL) and molecular sieves 4 A (2.0 g) inmethylene chloride (15 mL) was added copper(II) acetate (1.00 g), andthe mixture was stirred for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow viscous substance (0.98 g, 70%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.35 (d, J=6.1, 3H), 1.38(d, J=6.4, 3H), 1.64-1.78 (m, 1H), 2.21 (s, 3H), 2.61-2.70 (m, 2H), 3.97(s, 2H), 5.27-5.40 (m, 1H), 6.76-8.03 (m, 11H)

325b)3-(6-isopropoxypyridin-3-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogencarbonate (2.57 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(6-isopropoxypyridin-3-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.98 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.40g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.81 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.32 (d, J=6.1, 6H),1.46-1.62 (m, 2H), 2.10 (s, 3H), 2.48-2.54 (m, 2H), 3.87 (s, 2H),5.21-5.34 (m, 1H), 6.84-8.22 (m, 11H), 12.37 (s, 1H)

Example 3262-{4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]phenoxy}propanamide

326a)2-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}propanamide

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.00 g) and 2-bromopropanamide (0.70 g) in N,N-dimethylformamide (10mL) was added cesium carbonate (1.50 g), and the mixture was stirred at80° C. for 15 hr. After allowing to cool, ethyl acetate and water wereadded to the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (1.03 g, 88%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.62 (d, J=6.8, 3H),1.65-1.76 (m, 2H), 2.17 (s, 3H), 2.61-2.68 (m, 2H), 3.96 (s, 2H), 4.69(q, J=6.7, 1H), 5.65 (s, 1H), 6.38 (s, 1H), 6.94-7.79 (m, 12H)

326b)2-{4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]phenoxy}propanamide

A mixture of hydroxylammonium chloride (1.41 g), sodium hydrogencarbonate (2.05 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,2-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}propanamide(1.03 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.39g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.36 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.63 g, 55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.2, 3H), 1.47 (d, J=6.8, 3H),1.49-1.61 (m, 2H), 2.06 (s, 3H), 2.46-2.53 (m, 2H), 3.86 (s, 2H), 4.69(q, J=6.7, 1H), 6.98-7.74 (m, 14H), 12.36 (s, 1H)

Example 327

2-{4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]phenoxy}propanenitrile

To a solution of2-{4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]phenoxy}propanamide(0.57 g) and triethylamine (0.42 mL) in acetonitrile (5 mL) was addedtrifluoroacetic anhydride (0.28 mL), and the mixture was stirred for 12hr. Ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.35 g,64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.2, 3H), 1.44-1.63 (m, 2H), 1.73(d, J=6.8, 3H), 2.07 (s, 3H), 2.46-2.56 (m, 2H), 3.87 (s, 2H), 5.54 (q,J=6.4, 1H), 7.18-7.73 (m, 12H), 12.37 (s, 1H)

Example 328

3-(6-isopropoxypyridin-3-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-(6-isopropoxypyridin-3-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.54 g) in ethanol (3 mL) was added 8 M potassium hydroxide solution(0.13 mL), and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.54 g, 93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3, 3H), 1.33 (d, J=6.2, 6H),1.50-1.69 (m, 2H), 2.09 (s, 3H), 2.48-2.58 (m, 2H), 3.82 (s, 2H),5.21-5.35 (m, 1H), 6.84-8.21 (m, 11H)

Example 329

2-{4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]phenoxy}propanenitrilepotassium salt

To a solution of2-{4-[2-methyl-6-oxo-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-4-propylpyrimidin-1(6H)-yl]phenoxy}propanenitrile(0.54 g) in ethanol (3 mL) was added 8 M potassium hydroxide solution(0.13 mL), and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.54 g, 93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.24 (t, J=7.3, 3H), 0.82-0.97 (m, 2H), 1.03(d, J=6.8, 3H), 1.36 (s, 3H), 1.78-1.89 (m, 2H), 3.13 (s, 2H), 4.84 (q,J=6.6, 1H), 6.43-6.80 (m, 12H)

Example 330

2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]pyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.00 g), tetrahydro-2H-pyran-4-ol (0.44 mL) and triphenylphosphine(1.21 g) in tetrahydrofuran (5 mL) was added diisopropylazodicarboxylate (1.9 M toluene solution, 0.91 mL), and the mixture wasstirred for 1 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was crudely purifiedby silica gel column chromatography. This was added to a mixture ofhydroxylammonium chloride (1.90 g), sodium hydrogen carbonate (2.90 g)and dimethyl sulfoxide (10 mL), which had been stirred at 40° C. for 30min, and the mixture was stirred at 90° C. for 18 hr. The reactionmixture was allowed to cool to room temperature, ethyl acetate and waterwere added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.45 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.81 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.46-1.69 (m, 4H),1.95-2.11 (m, 5H), 2.45-2.54 (m, 2H), 3.44-3.55 (m, 2H), 3.81-3.91 (m,4H), 4.57-4.70 (m, 1H), 7.04-7.74 (m, 12H), 12.38 (s, 1H)

Example 331

2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]pyrimidin-4(3H)-onepotassium salt

To a solution of2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]pyrimidin-4(3H)-one(0.58 g) in ethanol (3 mL) was added 8 M potassium hydroxide solution(0.13 mL), and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.61 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.46-1.69 (m, 4H),1.95-2.11 (m, 5H), 2.45-2.54 (m, 2H), 3.44-3.55 (m, 2H), 3.81-3.91 (m,4H), 4.57-4.70 (m, 1H), 7.04-7.74 (m, 12H), 12.38 (s, 1H)

Example 332

3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g), (2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (0.30 g) andtriphenylphosphine (0.60 g) in tetrahydrofuran (3 mL) was addeddiisopropyl azodicarboxylate (1.9 M toluene solution, 1.21 mL), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wascrudely purified by silica gel column chromatography. This was added toa mixture of hydroxylammonium chloride (0.96 g), sodium hydrogencarbonate (1.45 g) and dimethyl sulfoxide (6 mL), which had been stirredat 40° C. for 30 min, and the mixture was stirred at 90° C. for 18 hr.The reaction mixture was allowed to cool to room temperature, ethylacetate and water were added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was dissolved in tetrahydrofuran (6 mL).N,N′-carbonyldiimidazole (0.22 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.43 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.08 (s, 3H), 1.10 (s,3H), 1.36-1.63 (m, 4H), 1.81-1.90 (m, 2H), 2.07 (s, 3H), 2.47-2.54 (m,2H), 3.77-3.90 (m, 4H), 4.81-4.87 (m, 1H), 7.04-7.73 (m, 12H), 12.38 (s,1H)

Example 333

3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.30 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.063 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.28 g, 86%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.46-1.69 (m, 4H),1.95-2.11 (m, 5H), 2.45-2.54 (m, 2H), 3.44-3.55 (m, 2H), 3.81-3.91 (m,4H), 4.57-4.70 (m, 1H), 7.04-7.74 (m, 12H), 12.38 (s, 1H)

Example 3343-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

334a)3-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(3.00 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (3.20 g) andtriphenylphosphine (3.60 g) in tetrahydrofuran (20 mL) was addeddiisopropyl azodicarboxylate (1.9 M toluene solution, 7.3 mL), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wascrudely purified by silica gel column chromatography. This was added toa mixture of hydroxylammonium chloride (3.00 g), sodium hydrogencarbonate (5.80 g) and dimethyl sulfoxide (16 mL), which had beenstirred at 40° C. for 30 min, and the mixture was stirred at 90° C. for18 hr. The reaction mixture was allowed to cool to room temperature,ethyl acetate and water were added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (20 mL).N,N′-carbonyldiimidazole (0.59 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.54 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (1.74 g, 88%).

¹H NMR (300 MHz, CDCl₃) δ 0.06 (s, 6H), 0.89-0.92 (m, 9H), 1.03 (t,J=7.3, 3H), 1.41-2.02 (m, 10H), 2.11 (s, 3H), 2.62-2.69 (m, 2H),3.74-3.88 (m, 3H), 4.24-4.35 (m, 1H), 6.88-7.74 (m, 12H), 8.86 (s, 1H)

334b)3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(1.74 g) in tetrahydrofuran (6 mL) was added tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 3.7 mL), and the mixture was stirred at60° C. for 12 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.99 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.26-2.10 (m, 13H),2.45-2.55 (m, 2H), 3.47-3.71 (m, 1H), 3.86 (s, 2H), 4.30-4.64 (m, 2H),7.01-7.72 (m, 12H), 12.37 (s, 1H)

Example 335

2-methyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.49 g) in methylene chloride (4 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.52 g),and the mixture was stirred for 2 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.38 g, 79%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.46-1.64 (m, 2H),1.97-2.55 (m, 13H), 3.87 (s, 2H), 4.81-4.94 (m, 1H), 7.13-7.73 (m, 12H),12.39 (s, 1H)

Example 336

3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.30 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.063 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.29 g, 93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3, 3H), 1.21-2.10 (m, 13H),2.44-2.62 (m, 2H), 3.47-3.68 (m, 1H), 3.81 (s, 2H), 4.31-4.80 (m, 2H),7.00-7.51 (m, 12H)

Example 337

2-methyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of2-methyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.30 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.063 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.31 g, 98%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3, 3H), 1.51-1.68 (m, 2H),1.99-2.23 (m, 7H), 2.31-2.58 (m, 6H), 3.82 (s, 2H), 4.83-4.92 (m, 1H),7.11-7.51 (m, 12H)

Example 338

3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

To a solution of3′-fluoro-4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g), (2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (0.29 g) andtriphenylphosphine (0.58 g) in tetrahydrofuran (2 mL) was addeddiisopropyl azodicarboxylate (1.9 M toluene solution, 1.16 mL), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wascrudely purified by silica gel column chromatography. This was added toa mixture of hydroxylammonium chloride (1.15 g), sodium hydrogencarbonate (1.85 g) and dimethyl sulfoxide (6 mL), which had been stirredat 40° C. for 30 min, and the mixture was stirred at 90° C. for 18 hr.The reaction mixture was allowed to cool to room temperature, ethylacetate and water were added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was dissolved in tetrahydrofuran (6 mL).N,N′-carbonyldiimidazole (0.21 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.52 g, 76%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.08 (d, J=6.2, 6H),1.36-1.63 (m, 4H), 1.79-1.90 (m, 2H), 2.08 (s, 3H), 3.75-3.89 (m, 4H),4.80-4.87 (m, 1H), 6.97-7.74 (m, 11H), 12.47 (s, 1H)

Example 339

3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one(0.30 g) in ethanol (3 mL) was added 8 M potassium hydroxide solution(0.060 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.27 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.08 (d, J=6.4, 6H),1.35-1.67 (m, 4H), 1.80-1.90 (m, 2H), 2.07 (s, 3H), 2.47-2.55 (m, 2H),3.76-3.90 (m, 4H), 4.79-4.88 (m, 1H), 6.98-7.52 (m, 11H)

Example 340

3-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-[4-(2-hydroxy-1-methylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.10 g) in ethanol (1 mL) was added 8 M potassium hydroxide solution(0.023 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.11 g, 100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.24 (d, J=6.1, 3H),1.46-1.70 (m, 2H), 2.06 (s, 3H), 2.42-2.62 (m, 2H), 3.42-3.64 (m, 2H),3.81 (s, 2H), 4.37-4.57 (m, 1H), 4.68-5.13 (m, 1H), 6.95-7.51 (m, 12H)

Example 3415-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-propylpyrimidin-4(3H)-one

341a) methyl2-{4-[5-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate

To a solution of3′-fluoro-4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g) and methyl 2-bromo-2-methylpropanoate (1.00 g) inN,N-dimethylformamide (5 mL) was added cesium carbonate (0.72 g), andthe mixture was stirred at 80° C. for 12 hr. After allowing to cool,ethyl acetate and water were added to the reaction mixture, and themixture was extracted with ethyl acetate. The organic layer was washedwith saturated brine and dried over anhydrous magnesium sulfate. Thesolvent was evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow amorphoussolid (0.58 g, 96%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.3, 3H), 1.60-1.78 (m, 8H), 2.16(s, 3H), 2.59-2.68 (m, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 6.89-7.78 (m,11H)

341b)3′-fluoro-4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of methyl2-{4-[5-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate(1.00 g) in tetrahydrofuran (11 mL) was added lithium tetrahydroborate(0.056 g), and the mixture was stirred for 24 hr. Ethyl acetate andwater were added, to the reaction mixture and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brineand dried over anhydrous magnesium sulfate. The solvent was evaporatedand the residue was purified by silica gel column chromatography to givethe title compound as a pale-yellow amorphous solid (0.41 g, 73%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.33 (s, 6H), 1.59-1.77(m, 2H), 2.13 (t, J=6.6, 1H), 2.17 (s, 3H), 2.61-2.67 (m, 2H), 3.62 (d,J=6.4, 2H), 3.99 (s, 2H), 7.09-7.78 (m, 11H)

341c)5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.81 g), sodium hydrogencarbonate (1.29 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.41 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.15g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.14 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.28 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.2, 3H), 1.24 (s, 6H), 1.47-1.64(m, 2H), 2.07 (s, 3H), 2.46-2.53 (m, 2H), 3.41 (d, J=5.3, 2H), 3.86 (s,2H), 4.96 (t, J=5.7, 1H), 6.99-7.74 (m, 11H), 12.47 (s, 1H)

Example 342

5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-propylpyrimidin-4(3H)-one(0.20 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.043 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.21 g, 98%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3, 3H), 1.24 (s, 6H), 1.50-1.68(m, 2H), 2.06 (s, 3H), 2.48-2.57 (m, 2H), 3.41 (s, 2H), 3.82 (s, 2H),6.99-7.55 (m, 11H)

Example 343

5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-6-propylpyrimidin-4(3H)-one

To a solution of3′-fluoro-4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.23 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.25 g) andtriphenylphosphine (1.42 g) in tetrahydrofuran (5 mL) was addeddiisopropyl azodicarboxylate (1.9 M toluene solution, 2.9 mL), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wascrudely purified by silica gel column chromatography. This was added toa mixture of hydroxylammonium chloride (2.26 g), sodium hydrogencarbonate (3.42 g) and dimethyl sulfoxide (14 mL), which had beenstirred at 40° C. for 30 min, and the mixture was stirred at 90° C. for18 hr. The reaction mixture was allowed to cool to room temperature,ethyl acetate and water were added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (14 mL).N,N′-carbonyldiimidazole (0.57 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.54 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (6 mL), tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 3.7 mL) was added, and the mixture was stirredat 60° C. for 12 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.71 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.28-1.94 (m, 10H),2.06-2.10 (m, 3H), 2.45-2.53 (m, 2H), 3.47-3.69 (m, 1H), 3.85 (s, 2H),4.29-4.63 (m, 2H), 6.95-7.75 (m, 11H), 12.44 (s, 1H)

Example 344

3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.00 g), 3-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.06 g) andtriphenylphosphine (1.21 g) in tetrahydrofuran (5 mL) was addeddiisopropyl azodicarboxylate (1.9 M toluene solution, 2.4 mL), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wascrudely purified by silica gel column chromatography. This was added toa mixture of hydroxylammonium chloride (1.90 g), sodium hydrogencarbonate (2.90 g) and dimethyl sulfoxide (12 mL), which had beenstirred at 40° C. for 30 min, and the mixture was stirred at 90° C. for18 hr. The reaction mixture was allowed to cool to room temperature,ethyl acetate and water were added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (12 mL).N,N′-carbonyldiimidazole (0.49 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (6 mL), tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 3.5 mL) was added, and the mixture was stirredat 60° C. for 12 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.69 g, 50%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.04-2.34 (m, 13H),2.46-2.54 (m, 2H), 3.45-3.97 (m, 3H), 4.24-4.79 (m, 2H), 6.99-7.73 (m,12H), 12.37 (s, 1H)

Example 3453-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

345a)4′-{[1-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) and cyclohexene oxide (1.20 mL) in N,N-dimethylformamide (10 mL)was added cesium carbonate (2.25 g), and the mixture was stirred at 100°C. for 20 hr. After allowing to cool, ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (0.93 g, 76%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.23-1.51 (m, 4H),1.61-1.84 (m, 4H), 2.06-2.23 (m, 5H), 2.56 (d, J=1.5, 1H), 2.59-2.71 (m,2H), 3.68-3.80 (m, 1H), 3.96 (s, 2H), 3.98-4.09 (m, 1H), 7.01-7.77 (m,12H)

345b)3-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.46 g), sodium hydrogencarbonate (2.21 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.94 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.34g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.077 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.20-2.14 (m, 13H),2.45-2.54 (m, 2H), 3.48-3.60 (m, 1H), 3.86 (s, 2H), 4.04-4.15 (m, 1H),4.93 (d, J=4.3, 1H), 7.04-7.73 (m, 12H), 12.37 (s, 1H)

Example 346

5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-6-propylpyrimidin-4(3H)-one

To a solution of5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-6-propylpyrimidin-4(3H)-one(0.40 g) in methylene chloride (4 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.42 g),and the mixture was stirred for 15 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.35 g, 88%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.2, 3H), 1.48-1.64 (m, 2H),1.97-2.23 (m, 7H), 2.29-2.49 (m, 6H), 3.86 (s, 2H), 4.81-4.93 (m, 1H),6.97-7.75 (m, 11H), 12.46 (s, 1H)

Example 347

2-methyl-3-{4-[(3-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.40 g) in methylene chloride (4 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.43 g),and the mixture was stirred for 15 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.33 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.47-1.62 (m, 2H),1.71-2.12 (m, 7H), 2.22-2.86 (m, 6H), 3.86 (s, 2H), 4.95-5.03 (m, 1H),7.00-7.73 (m, 12H), 12.38 (s, 1H)

Example 348

2-methyl-3-{4-[(2-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.30 g) in methylene chloride (3 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.32 g),and the mixture was stirred for 15 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.27 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 2.23-2.77 (m, 5H), 3.86(s, 2H), 5.05-5.14 (m, 1H), 6.92-7.73 (m, 12H), 12.37 (s, 1H)

Example 349

5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-6-propylpyrimidin-4(3H)-one(0.20 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.041 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.19 g, 86%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3, 3H), 1.25-2.11 (m, 10H),2.47-2.54 (m, 2H), 3.46-3.68 (m, 1H), 3.81 (s, 2H), 4.31-4.65 (m, 2H),6.96-7.54 (m, 11H)

Example 350

3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.20 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.041 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.19 g, 86%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3, 3H), 1.07-2.34 (m, 10H),2.47-2.56 (m, 2H), 3.44-3.97 (m, 3H), 4.23-4.79 (m, 2H), 6.97-7.50 (m,12H)

Example 351

3-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-(4-{[(1S,2S)-2-hydroxycyclohexyl]oxy}phenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.20 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.042 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.18 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3, 3H), 1.21-2.12 (m, 13H),2.46-2.58 (m, 2H), 3.46-3.64 (m, 1H), 3.82 (s, 2H), 4.02-4.16 (m, 1H),4.89-5.00 (m, 1H), 7.00-7.51 (m, 12H)

Example 352

5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-6-propylpyrimidin-4(3H)-one(0.20 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.041 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a pale-yellow amorphous solid (0.18 g, 86%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.3, 3H), 1.50-1.70 (m, 2H),1.94-2.58 (m, 13H), 3.82 (s, 2H), 4.81-4.94 (m, 1H), 6.98-7.53 (m, 11H)

Example 353

2-methyl-3-{4-[(2-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of2-methyl-3-{4-[(2-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.20 g) in ethanol (1.5 mL) was added 8 M potassium hydroxide solution(0.042 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a pale-yellow amorphous solid (0.19 g, 88%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3, 3H), 1.49-2.74 (m, 15H),3.81 (s, 2H), 5.03-5.15 (m, 1H), 6.91-7.50 (m, 12H)

Example 354

3-{4-[(4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.00 g), 1-methylcyclohexane-1,4-diol (0.60 g) and triphenylphosphine(1.21 g) in tetrahydrofuran (5 mL) was added diisopropylazodicarboxylate (1.9 M toluene solution, 2.42 mL), and the mixture wasstirred for 1 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was crudely purifiedby silica gel column chromatography. This was added to a mixture ofhydroxylammonium chloride (0.73 g), sodium hydrogen carbonate (1.20 g)and dimethyl sulfoxide (4 mL), which had been stirred at 40° C. for 30min, and the mixture was stirred at 90° C. for 18 hr. The reactionmixture was allowed to cool to room temperature, ethyl acetate and waterwere added, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.25 g, 17%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.15 (s, 3H), 1.35-1.71(m, 8H), 1.85-1.98 (m, 2H), 2.06 (s, 3H), 2.47-2.54 (m, 2H), 3.86 (s,2H), 4.20 (s, 1H), 4.51-4.59 (m, 1H), 7.01-7.72 (m, 12H), 12.38 (s, 1H)

Example 355

3-{4-[(4-hydroxy-3-methylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.00 g), 4-hydroxy-2-methylcyclohexanone (1.18 g) andtriphenylphosphine (2.42 g) in tetrahydrofuran (10 mL) was addeddiisopropyl azodicarboxylate (1.9 M toluene solution, 4.84 mL), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wascrudely purified by silica gel column chromatography. This was dissolvedin ethanol (20 mL), sodium tetrahydroborate (0.17 g) was added, and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue was addedto a mixture of hydroxylammonium chloride (1.27 g), sodium hydrogencarbonate (1.85 g) and dimethyl sulfoxide (10 mL), which had beenstirred at 40° C. for 30 min, and the mixture was stirred at 90° C. for18 hr. The reaction mixture was allowed to cool to room temperature,ethyl acetate and water were added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (8 mL).N,N′-carbonyldiimidazole (0.36 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.91 g, 33%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82-1.00 (m, 6H), 1.22-2.16 (m, 12H),2.46-2.54 (m, 2H), 2.93-3.11 (m, 1H), 3.86 (s, 2H), 4.26-4.71 (m, 2H),6.98-7.73 (m, 12H), 12.37 (s, 1H)

Example 356

2-methyl-3-{4-[(3-methyl-4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-{4-[(4-hydroxy-3-methylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.50 g) in methylene chloride (4 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.52 g),and the mixture was stirred for 1 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.38 g, 77%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.99 (m, 6H), 1.43-1.63 (m, 2H),1.67-2.93 (m, 12H), 3.87 (s, 2H), 4.81-5.04 (m, 1H), 7.10-7.73 (m, 12H),12.38 (s, 1H)

Example 357

3-{4-[(4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-{4-[(4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.20 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.041 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.18 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.3, 3H), 1.15 (s, 3H), 1.32-2.00(m, 10H), 2.05 (s, 3H), 2.46-2.57 (m, 2H), 3.81 (s, 2H), 4.48-4.59 (m,1H), 6.99-7.50 (m, 12H)

Example 358

3-{4-[(4-hydroxy-3-methylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-{4-[(4-hydroxy-3-methylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.30 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.061 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a colorless amorphous solid (0.30 g, 96%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86-0.99 (m, 6H), 1.23-2.11 (m, 12H),2.47-2.57 (m, 2H), 2.93-3.13 (m, 1H), 3.81 (s, 2H), 4.27-4.69 (m, 2H),6.98-7.50 (m, 12H)

Example 359

2-methyl-3-{4-[(3-methyl-4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

To a solution of2-methyl-3-{4-[(3-methyl-4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.30 g) in ethanol (2.0 mL) was added 8 M potassium hydroxide solution(0.062 mL), and the mixture was stirred at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure, and theresidue was triturated with diisopropyl ether to give the title compoundas a pale-yellow amorphous solid (0.31 g, 96%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89-0.97 (m, 6H), 1.44-2.90 (m, 14H), 3.82(s, 2H), 4.84-5.02 (m, 1H), 7.08-7.49 (m, 12H)

Example 360

3-{4-[(4-hydroxy-3,3-dimethylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.00 g), 4-{[tert-butyl(dimethyl)silyl]oxy}-3,3-dimethylcyclohexanol(1.13 g) and triphenylphosphine (1.15 g) in tetrahydrofuran (5 mL) wasadded diisopropyl azodicarboxylate (1.9 M toluene solution, 2.30 mL),and the mixture was stirred for 1 hr. Ethyl acetate and water were addedto the reaction mixture, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was crudely purified by silica gel column chromatography. Thiswas added to a mixture of hydroxylammonium chloride (1.60 g), sodiumhydrogen carbonate (2.32 g) and dimethyl sulfoxide (10 mL), which hadbeen stirred at 40° C. for 30 min, and the mixture was stirred at 90° C.for 18 hr. The reaction mixture was allowed to cool to room temperature,ethyl acetate and water were added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine anddried over anhydrous magnesium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.41 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (6 mL), tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 5.8 mL) was added, and the mixture was stirredat 60° C. for 12 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.65 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-0.98 (m, 9H), 1.45-1.84 (m, 8H), 2.07(s, 3H), 2.46-2.54 (m, 2H), 3.20-3.27 (m, 1H), 3.86 (s, 2H), 4.43-4.60(m, 2H), 6.98-7.73 (m, 12H), 12.37 (s, 1H)

Example 361

3-{4-[(3,3-dimethyl-4-oxocyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-{4-[(4-hydroxy-3,3-dimethylcyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.33 g) in methylene chloride (3 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.34 g),and the mixture was stirred for 1 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.20 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.06 (s, 3H), 1.20 (s,3H), 1.47-1.62 (m, 2H), 1.78-1.91 (m, 2H), 3.87 (s, 2H), 4.94-5.05 (m,1H), 7.10-7.73 (m, 12H), 12.39 (s, 1H)

Example 3622-ethyl-3-(4-isopropoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

362a)4′-{[2-ethyl-1-(4-isopropoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 4-isopropoxyphenylboronic acid (0.5 g), triethylamine (0.97mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) indichloromethane (10 mL) was added copper(II) acetate (0.51 g), and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate, the insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowsolid (0.51 g, 77%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.5), 1.14 (3H, t, J=7.5), 1.36(6H, d, J=6.0), 1.65-1.79 (2H, m), 2.39 (2H, q, J=7.5), 2.67 (2H, t,J=7.5), 3.97 (2H, s), 4.49-4.64 (1H, m), 6.98 (2H, d, J=8.7), 7.10 (2H,d, J=8.7), 7.36-7.51 (6H, m), 7.57-7.66 (1H, m), 7.74 (1H, d, J=7.8)

362b)2-ethyl-3-(4-isopropoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-ethyl-1-(4-isopropoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.51 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.36 g, 63%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.5), 1.05 (3H, t, J=7.2),1.30 (6H, d, J=6.0), 1.50-1.65 (2H, m), 2.28 (2H, q, J=7.2), 2.45-2.58(2H, m), 3.86 (2H, s), 4.61-4.74 (1H, m), 7.02 (2H, d, J=9.0), 7.18-7.32(6H, m), 7.46-7.58 (2H, m), 7.61-7.72 (2H, m), 12.39 (1H, br)

Example 3632-ethyl-3-(3-fluoro-4-isopropoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

363a)4′-{[2-ethyl-1-(3-fluoro-4-isopropoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 3-fluoro-4-isopropoxyphenylboronic acid (0.55 g), triethylamine(0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) indichloromethane (10 mL) was added copper(II) acetate (0.51 g), and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate, the insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowsolid (0.43 g, 61%).

¹H NMR (300 MHz, CDCl₃) δ 1.10 (3H, t, J=7.5), 1.16 (3H, t, J=7.5),1.35-1.45 (6H, m), 1.64-1.80 (2H, m), 2.39 (2H, q, J=7.5), 2.61-2.71(2H, m), 3.96 (2H, s), 4.52-4.66 (1H, m), 6.89-7.11 (3H, m), 7.37-7.51(6H, m), 7.57-7.66 (1H, m), 7.74 (1H, d, J=7.8)

363b)2-ethyl-3-(3-fluoro-4-isopropoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-ethyl-1-(3-fluoro-4-isopropoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.43 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.23 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.06 (3H, t, J=7.2),1.20-1.35 (6H, m), 1.49-1.65 (2H, m), 2.31 (2H, q, J=7.2), 2.46-2.58(2H, m), 3.87 (2H, s), 4.65-4.79 (1H, m), 7.09-7.44 (7H, m), 7.46-7.58(2H, m), 7.61-7.72 (2H, m), 12.38 (1H, br)

Example 3643-(4-tert-butoxyphenyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

364a)4′-{[1-(4-tert-butoxyphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 4-tert-butoxyphenylboronic acid (0.54 g), triethylamine (0.97mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) indichloromethane (10 mL) was added copper(II) acetate (0.51 g), and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate, the insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowsolid (0.47 g, 66%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.5), 1.13 (3H, t, J=7.5), 1.39(9H, s), 1.64-1.79 (2H, m), 2.36 (2H, q, J=7.5), 22.62-2.71 (2H, m),3.97 (2H, s), 7.07-7.14 (4H, m), 7.35-7.51 (6H, m), 7.57-7.66 (1H, m),7.74 (1H, d, J=7.8)

364b)3-(4-tert-butoxyphenyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-tert-butoxyphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.47 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.28 g, 54%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.35 (9H, s), 1.51-1.65 (2H, m), 2.28 (2H, q, J=7.2), 2.51-2.59 (2H, m),3.87 (2H, s), 7.09 (2H, d, J=8.7), 7.17-7.31 (6H, m), 7.46-7.58 (2H, m),7.61-7.71 (2H, m), 12.39 (1H, br)

Example 3652-ethyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

365a)4′-{[1-(3-acetylphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), 3-acetylphenylboronic acid (1.0 g), triethylamine (2.0 mL),pyridine (1.1 mL) and molecular sieves 4 A (2 g) in dichloromethane (20mL) was added copper(II) acetate (1.0 g), and the mixture was stirredfor 2 days. The reaction mixture was diluted with ethyl acetate, theinsoluble material was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.63 g,47%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.5), 1.15 (3H, t, J=7.5),1.66-1.81 (2H, m), 2.27-2.39 (2H, m), 2.63 (3H, s), 2.65-2.74 (2H, m),3.97 (2H, s), 7.37-7.52 (7H, m), 7.57-7.69 (2H, m), 7.71-7.77 (1H, m),7.82 (1H, s), 8.05 (1H, d, J=6.3)

365b)4′-({2-ethyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(3-acetylphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.63 g) in tetrahydrofuran (10 mL) was added methyllithium (1.2 mL, 2.2M diethyl ether solution) under ice-cooling, and the mixture was stirredfor 1 hr. A saturated aqueous ammonium chloride solution was added tothe reaction mixture, and the mixture was extracted with ethyl acetate,washed with saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as apale-yellow solid (0.54 g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.5), 1.14 (3H, t, J=7.5), 1.59(3H, s), 1.61 (3H, s), 1.65-1.81 (2H, m), 2.01 (1H, s), 2.34 (2H, q,J=7.5), 2.63-2.74 (2H, m), 3.89-4.05 (2H, m), 7.10 (1H, d, J=7.5),7.35-7.66 (10H, m), 7.73 (1H, d, J=7.8)

365c)2-ethyl-3-[3-(1-hydroxy-1-methylethyl)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({2-ethyl-1-[3-(1-hydroxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.22 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.39 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.5), 1.04 (3H, t, J=7.2),1.44 (6H, s), 1.50-1.68 (2H, m), 2.25 (2H, q, J=7.2), 2.51-2.60 (2H, m),3.88 (2H, s), 5.14 (1H, s), 7.13-7.33 (5H, m), 7.36-7.73 (7H, m), 12.39(1H, br)

Example 3663-(4-tert-butoxyphenyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

366a)4′-{[1-(4-tert-butoxyphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 4-tert-butoxyphenylboronic acid (0.54 g), triethylamine (0.97mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) indichloromethane (10 mL) was added copper(II) acetate (0.54 g), and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate, the insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowsolid (0.51 g, 72%).

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.2), 1.30-1.49 (11H, m),1.55-1.68 (2H, m), 2.10 (3H, s), 2.61-2.71 (2H, m), 3.97 (2H, s),7.07-7.15 (4H, m), 7.36-7.51 (6H, s), 7.51-7.65 (1H, m), 7.74 (1H, d,J=7.8)

366b)3-(4-tert-butoxyphenyl)-6-butyl-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-tert-butoxyphenyl)-4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.51 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.27 g, 48%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.26-1.39 (11H, m),1.42-1.57 (2H, m), 2.06 (3H, s), 2.50-2.59 (2H, m), 3.86 (2H, s), 7.10(2H, d, J=8.7), 7.18-7.31 (6H, m), 7.45-7.57 (2H, m), 7.61-7.71 (2H, m),12.41 (1H, br)

Example 3673-[4-(2,2-dimethylpropoxy)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

367a)4′-({1-[4-(2,2-dimethylpropoxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.4 g) in N,N-dimethylacetamide (10 mL) were added1-iodo-2,2-dimethylpropane (0.26 g) and cesium carbonate (0.44 g), andthe mixture was stirred at 120° C. for 24 hr. The mixture was allowed tocool to room temperature and the insoluble material was filtered off.The filtrate was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, saturated sodium hydrogen carbonate and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound as a pale-yellow solid(0.40 g, 87%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.04 (9H, s), 1.14 (3H,t, J=7.2), 1.63-1.79 (2H, m), 2.39 (2H, q, J=7.2), 2.61-2.72 (2H, m),3.62 (2H, s), 3.97 (2H, s), 7.01 (2H, d, J=8.7), 7.11 (2H, d, J=8.7),7.36-7.51 (6H, m), 7.57-7.65 (1H, m), 7.74 (1H, d, J=7.8)

367b)3-[4-(2,2-dimethylpropoxy)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.91 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2,2-dimethylpropoxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.46 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.33 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 0.98-1.09 (12H, m),1.50-1.66 (2H, m), 2.28 (2H, q, J=7.2), 2.50-2.58 (2H, m), 3.69 (2H, s),3.87 (2H, s), 7.05 (2H, d, J=9.0), 7.18-7.32 (6H, m), 7.46-7.58 (2H, m),7.61-7.71 (2H, m), 12.39 (1H, br)

Example 3683-(4-isopropoxyphenyl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

368a)4′-{[1-(4-isopropoxyphenyl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 4-isopropoxyphenylboronic acid (0.56 g), triethylamine (0.97mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) indichloromethane (10 mL) was added copper(II) acetate (0.51 g), and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate, the insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowsolid (0.56 g, 82%).

¹H NMR (300 MHz, CDCl₃) δ 1.10 (3H, t, J=7.5), 1.35 (6H, d, J=6.3),1.64-1.79 (2H, m), 2.57-2.66 (2H, m), 3.88 (3H, s), 3.93 (2H, s),4.49-4.62 (1H, m), 6.90 (2H, d, J=9.0), 7.10 (2H, d, J=9.0), 7.35-7.52(6H, m), 7.57-7.75 (1H, m), 7.74 (1H, d, J=7.8)

368b)3-(4-isopropoxyphenyl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.4 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-isopropoxyphenyl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.56 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.13 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.21 g, 33%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.29 (6H, d, J=6.0),1.49-1.66 (2H, m), 2.46-2.56 (2H, m), 3.81 (3H, s), 3.83 (2H, s),4.57-4.71 (1H, m), 6.97 (2H, d, J=9.0), 7.14-7.30 (6H, m), 7.46-7.58(2H, m), 7.60-7.71 (2H, m), 12.41 (1H, br)

Example 3693-(4-tert-butoxyphenyl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

369a)4′-{[1-(4-tert-butoxyphenyl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 4-tert-butoxyphenylboronic acid (0.54 g), triethylamine (0.97mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) indichloromethane (10 mL) was added copper(II) acetate (0.51 g), and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate, the insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.53 g, 75%).

¹H NMR (300 MHz, CDCl₃) δ 1.10 (3H, t, J=7.5), 1.38 (9H, s), 1.64-1.80(2H, m), 2.56-2.66 (2H, m), 3.88 (3H, s), 3.94 (2H, s), 7.02-7.14 (4H,m), 7.34-7.52 (6H, m), 7.56-7.66 (1H, m), 7.73 (1H, d, J=7.8)

369b)3-(4-tert-butoxyphenyl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-tert-butoxyphenyl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.53 g) was added, and the mixture was stirred at 90° C. for 5 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.10 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.095 mL) were added, and themixture was stirred at room temperature for 30 min. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.16 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.2), 1.35 (9H, s), 1.50-1.67(2H, m), 2.44-2.58 (2H, m), 3.82 (5H, s), 7.05 (2H, d, J=9.0), 7.14-7.31(6H, m), 7.45-7.58 (2H, m), 7.58-7.73 (2H, m), 12.39 (1H, br)

Example 370

3-[4-(2,2-dimethylpropoxy)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(4H)-onepotassium salt

To a solution of3-[4-(2,2-dimethylpropoxy)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.15 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.032 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.15 g, 91%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.2), 0.98-1.08 (12H, m),1.54-1.71 (2H, m), 2.27 (2H, q, J=7.2), 2.51-2.61 (2H, m), 3.68 (2H, s),3.82 (2H, s), 7.04 (2H, d, J=9.0), 7.11-7.49 (10H, m)

Example 371

3-(4-isopropoxyphenyl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(4H)-onepotassium salt

To a solution of3-(4-isopropoxyphenyl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.15 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.035 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.15 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.2), 1.29 (6H, d, J=6.0),1.56-1.70 (2H, m), 2.48-2.57 (2H, m), 3.78 (2H, s), 3.80 (3H, s),4.57-4.71 (1H, m), 6.96 (2H, d, J=9.0), 7.11-7.23 (6H, m), 7.25-7.49(4H, m)

Example 372

3-(4-tert-butoxyphenyl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(4H)-onepotassium salt

To a solution of3-(4-tert-butoxyphenyl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.12 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.026 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.10 g, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.95 (3H, t, J=7.2), 1.35 (9H, s), 1.56-1.71(2H, m), 2.50-2.57 (2H, m), 3.78 (2H, s), 3.81 (3H, s), 7.04 (2H, d,J=8.7), 7.11-7.24 (6H, m), 7.25-7.49 (4H, m)

Example 3732-ethyl-3-(6-isopropoxypyridin-3-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

373a)4′-{[2-ethyl-1-(6-isopropoxypyridin-3-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 6-isopropoxy-3-pyridylboronic acid (0.51 g), triethylamine(0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) indichloromethane (10 mL) was added copper(II) acetate (0.51 g), and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate, the insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.39 g, 56%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.17 (3H, t, J=7.2),1.31-1.42 (6H, m), 1.64-1.80 (2H, m), 2.30-2.48 (2H, m), 2.62-2.73 (2H,m), 3.96 (2H, s), 5.25-5.38 (1H, m), 6.80 (1H, d, J=8.7), 7.36-7.51 (7H,m), 7.57-7.66 (1H, m), 7.70-7.78 (1H, m), 7.99 (1H, d, J=2.4)

373b)2-ethyl-3-(6-isopropoxypyridin-3-yl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-ethyl-1-(6-isopropoxypyridin-3-yl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.39 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.30 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.5), 1.07 (3H, t, J=7.5),1.32 (6H, d, J=6.0), 1.50-1.66 (2H, m), 2.20-2.42 (2H, m), 2.52-2.59(2H, m), 3.87 (2H, s), 5.20-5.34 (1H, m), 6.89 (1H, d, J=8.7), 7.21 (2H,d, J=8.1), 7.28 (2H, d, J=8.1), 7.46-7.59 (2H, m), 7.61-7.79 (3H, m),8.16 (1H, s), 12.39 (1H, br)

Example 3742-ethyl-3-[4-(1-methoxy-1-methylethyl)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

374a)4′-{[1-(4-acetylphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.2 g), 4-acetylphenylboronic acid (1.1 g), triethylamine (2.2 mL),pyridine (1.3 mL) and molecular sieves 4 A (2.4 g) in dichloromethane(30 mL) was added copper(II) acetate (1.2 g), and the mixture wasstirred for 2 days. The reaction mixture was diluted with ethyl acetate,the insoluble material was filtered off through celite, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.78 g,51%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.2), 1.15 (3H, t, J=7.2),1.65-1.80 (2H, m), 2.34 (2H, q, J=7.2), 2.65 (3H, s), 2.66-2.73 (2H, m),3.97 (2H, s), 7.32-7.51 (8H, m), 7.58-7.65 (1H, m), 7.74 (1H, d, J=7.8),8.11 (2H, d, J=8.7)

374b)4′-({2-ethyl-1-[4-(1-hydroxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-acetylphenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.78 g) in tetrahydrofuran (20 mL) was added methyllithium (2.4 mL, 1.4M diethyl ether solution) under ice-cooling, and the mixture was stirredfor 1 hr. A saturated aqueous ammonium chloride solution was added tothe reaction mixture, and the mixture was extracted with ethyl acetate,washed with saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.30 g, 37%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.15 (3H, t, J=7.2), 1.61(6H, s), 2.66-1.79 (2H, m), 1.82 (1H, s), 2.36 (2H, q, J=7.2), 2.62-2.72(2H, m), 3.97 (2H, s), 7.19 (2H, d, J=8.7), 7.37-7.51 (6H, m), 7.57-7.68(3H, m), 7.74 (1H, d, J=7.5)

374c)4′-({2-ethyl-1-[4-(1-methoxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({2-ethyl-1-[4-(1-hydroxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.30 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.049g, 60%), and the mixture was stirred for 15 min. Then methyl iodide(0.076 mL) was added, and the mixture was further stirred for 2 hr.Small pieces of ice were added to the reaction mixture. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.10 g, 32%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.5), 1.15 (3H, t, J=7.5), 1.56(6H, s), 1.66-1.80 (2H, m), 2.36 (2H, q, J=7.5), 2.64-2.70 (2H, m), 3.12(3H, s), 3.97 (2H, s), 7.20 (2H, d, J=8.4), 7.36-7.51 (6H, m), 7.52-7.65(3H, m), 7.40 (1H, d, J=7.5)

374d)2-ethyl-3-[4-(1-methoxy-1-methylethyl)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogencarbonate (0.33 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,4′-({2-ethyl-1-[4-(1-methoxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.1 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.05 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.025 g, 22%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.50 (6H, s), 1.54-1.65 (2H, m), 2.26 (2H, q, J=7.2), 2.52-2.62 (2H, m),3.03 (3H, s), 3.86 (2H, s), 7.17-7.30 (4H, m), 7.30-7.37 (2H, m),7.44-7.56 (4H, m), 7.58-7.68 (2H, m), 12.44 (1H, br)

Example 3752-ethyl-3-[4-(2-methoxy-2-methylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

375a)4′-({2-ethyl-1-[4-(2-hydroxy-2-methylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.48 g) in N,N-dimethylacetamide (10 mL) were added 2,2-dimethyloxirane(0.77 g) and cesium carbonate (0.70 g), and the mixture was stirred at120° C. for 24 hr. The mixture was allowed to cool to room temperature.The insoluble material was filtered off, and the filtrate was dilutedwith ethyl acetate, washed with 1 M hydrochloric acid, saturated sodiumhydrogen carbonate and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel chromatography to give the title compound asa pale-yellow solid (0.36 g, 64%).

¹H NMR (300 MHz, CDCl₃) δ 1.09 (3H, t, J=7.2), 1.15 (3H, t, J=7.2), 1.36(6H, s), 1.65-1.79 (2H, m), 2.19 (1H, s), 2.37 (2H, q, J=7.2), 2.62-2.71(2H, m), 3.83 (2H, s), 3.97 (2H, s), 7.04 (2H, d, J=9.0), 7.14 (2H, d,J=9.0), 7.37-7.51 (6H, m), 7.58-7.65 (1H, m), 7.74 (1H, d, J=9.0)

375b)4′-({2-ethyl-1-[4-(2-methoxy-2-methylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({2-ethyl-1-[4-(2-hydroxy-2-methylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.33 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.05g, 60%), and the mixture was stirred for 15 min. Then methyl iodide(0.08 mL) was added, and the mixture was further stirred for 2 hr. Smallpieces of ice were added to the reaction mixture, and the mixture wasstirred for 15 min. The reaction mixture was diluted with ethyl acetate,washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (0.10 g, 29%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.14 (3H, t, J=7.2), 1.31(6H, s), 1.64-1.79 (2H, m), 2.38 (2H, q, J=7.2), 2.62-2.71 (2H, m), 3.31(3H, s), 3.85 (2H, s), 3.96 (2H, s), 7.05 (2H, d, J=9.0), 7.13 (2H, d,J=9.0), 7.36-7.51 (6H, m), 7.57-7.65 (1H, m), 7.73 (1H, d, J=7.8)

375c)2-ethyl-3-[4-(2-methoxy-2-methylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogencarbonate (0.33 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,4′-({2-ethyl-1-[4-(2-methoxy-2-methylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.1 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.05 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.048 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.23 (6H, s), 1.50-1.66 (2H, m), 2.28 (2H, q, J=7.2), 2.50-2.57 (2H, m),3.18 (3H, s), 3.87 (2H, s), 3.90 (2H, s), 7.08 (2H, q, J=9.0), 7.18-7.32(6H, m), 7.46-7.57 (2H, m), 7.60-7.72 (2H, m), 12.39 (1H, br)

Example 3762-ethyl-3-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

376a) ethyl2-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.5 g) in N,N-dimethylacetamide (20 mL) were added ethyl2-bromo-2-methylpropionate (0.98 g) and cesium carbonate (1.6 g), andthe mixture was stirred at 120° C. for 24 hr. The mixture was allowed tocool to room temperature, and the insoluble material was filtered off.The filtrate was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, saturated sodium hydrogen carbonate and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound as a colorless solid (1.6g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.2), 1.12 (3H, t, J=7.2), 1.25(3H, t, J=7.2), 1.63 (6H, s), 1.66-1.77 (2H, m), 2.34 (2H, q, J=7.2),2.61-2.70 (2H, m), 3.96 (2H, s), 4.25 (2H, q, J=7.2), 6.95 (2H, d,J=9.0), 7.08 (2H, d, J=9.0), 7.36-7.51 (6H, m), 7.57-7.66 (1H, m), 7.74(1H, d, J=7.8)

376b)4′-({2-ethyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of sodium borohydride (0.84 g) in ethanol (20mL)-tetrahydrofuran (20 mL) was added calcium chloride (1.2 g) underice-cooling, and the mixture was stirred for 15 min. A solution of ethyl2-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate(1.6 g) in tetrahydrofuran (20 mL) was added, and the mixture wasfurther stirred for 2 hr. Small pieces of ice were added in the reactionmixture, and the mixture was stirred for 15 min, and diluted with ethylacetate and 1 M hydrochloric acid. The organic layer was separated,washed with saturated sodium hydrogen carbonate and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel chromatographyto give the title compound as a colorless solid (1.0 g, 71%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.14 (3H, t, J=7.2), 1.33(6H, s), 1.64-1.80 (2H, m), 2.36 (2H, q, J=7.2), 2.62-2.71 (2H, m), 3.62(2H, d, J=5.7), 3.97 (2H, s), 7.08-7.18 (4H, m), 7.37-7.51 (6H, m),7.58-7.66 (1H, m), 7.74 (1H, d, J=7.8)

376c)4′-({2-ethyl-1-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({2-ethyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.48 g) in N,N-dimethylformamide (10 mL) was added sodium hydride (0.07g, 60%), and the mixture was stirred for 15 min. Then methyl iodide(0.11 mL) was added, and the mixture was further stirred for 2 hr. Smallpieces of ice were added to the reaction mixture, and the mixture wasstirred for 15 min, diluted with ethyl acetate, washed with 1 Mhydrochloric acid, saturated aqueous sodium hydrogen carbonate solutionand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.24 g, 48%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.2), 1.13 (3H, t, J=7.2), 1.34(6H, s), 1.65-1.79 (2H, m), 2.34 (2H, q, J=7.2), 2.62-2.70 (2H, m), 3.39(2H, s), 3.43 (3H, s), 3.97 (2H, s), 7.09-7.17 (4H, m), 7.37-7.50 (6H,m), 7.57-7.66 (1H, m), 7.74 (1H, d, J=7.5)

376d)2-ethyl-3-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogencarbonate (0.74 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({2-ethyl-1-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.24 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.11 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.16 g, 61%).

¹H NMR (300 MHz, CDCl₃) δ 1.03 (3H, t, J=7.2), 1.12 (3H, t, J=7.2), 1.33(6H, s), 1.69-1.85 (2H, m), 2.32 (2H, q, J=7.2), 2.65-2.75 (2H, m), 3.38(2H, s), 3.42 (3H, s), 3.89 (2H, s), 6.98-7.12 (4H, m), 7.20 (2H, d,J=8.1), 7.29 (2H, d, J=8.1), 7.37-7.49 (2H, m), 7.53-7.62 (1H, m), 7.75(1H, d, J=7.5)

Example 3772-ethyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

377a)4′-({1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({2-ethyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.49 g) and 2,6-lutidine (0.33 mL) in dichloromethane (10 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.32 mL) underice-cooling, and the mixture was stirred for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.50 g, 85%).

¹H NMR (300 MHz, CDCl₃) δ 0.08 (6H, s), 0.93 (9H, s), 1.10 (3H, t,J=7.2), 1.13 (3H, t, J=7.2), 1.30 (6H, s), 1.64-1.80 (2H, m), 2.36 (2H,q, J=7.2), 2.62-2.71 (2H, m), 3.59 (2H, s), 3.97 (2H, s), 7.06-7.18 (4H,m), 7.36-7.51 (6H, m), 7.58-7.65 (1H, m), 7.74 (1H, d, J=7.8)

377b)2-ethyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.93 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.5 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.18 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (10 mL), tetrabutylammonium fluoride (2.1 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was stirred for 2hr. The reaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.33 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.25 (6H, s), 1.49-1.66 (2H, m), 2.28 (2H, q, J=7.2), 2.51-2.58 (2H, m),3.41 (2H, d, J=5.7), 3.87 (2H, s), 4.96 (1H, t, J=5.7), 7.13 (2H, t,J=8.7), 7.19-7.32 (6H, m), 7.46-7.58 (2H, m), 7.60-7.72 (2H, m), 12.40(1H, br)

Example 378

2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]pyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.37 g), tetrahydro-4-pyranol (0.26 g) and triphenylphosphine (0.66 g)in tetrahydrofuran (1.5 mL) was added diisopropyl azodicarboxylate (1.3mL, 1.9 M toluene solution), and the mixture was stirred at roomtemperature for 12 hr. The reaction mixture was diluted with ethylacetate, washed with 1 M hydrochloric acid and then with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was crudely purified bysilica gel column chromatography. The crudely purified product wasdissolved in dimethyl sulfoxide (10 mL), hydroxylammonium chloride (0.98g) and sodium hydrogen carbonate (1.4 g) were added, and the mixture wasstirred at 90° C. for 24 hr. The mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and theprecipitated solid was collected by filtration. The obtained solid wasdissolved in ethyl acetate. The solution was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.20 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.17 g, 35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.50-1.69 (4H, m), 1.95-2.07 (2H, m), 2.28 (2H, q, J=7.2), 2.51-2.57(2H, m), 3.43-3.56 (4H, m), 3.81-3.92 (2H, m), 4.58-4.70 (1H, m), 7.10(2H, d, J=8.7), 7.16-7.31 (6H, m), 7.46-7.58 (2H, m), 7.61-7.72 (2H, m),12.40 (1H, br)

Example 3792-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-4-yloxy)pyrimidin-4(3H)-one

379a)4′-[(1-hydroxy-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), chlorotrimethylsilane (0.36 mL) and hexamethyldisilazane (20mL) was heated under reflux for 12 hr. The reaction mixture wasconcentrated, and the residue was dissolved in dichloromethane (20 mL).Molybdenum pentoxide/hexamethylphosphoramide/pyridine complex (2.3 g)was added, and the mixture was stirred at room temperature for 12 hr.The reaction mixture was diluted with ethyl acetate, saturatedtetrasodium ethylenediaminetetraacetate was added, and the mixture wasstirred for 2 hr. The organic layer was separated, washed with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.53 g, 50%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.45-1.62 (2H, m), 2.41(3H, s), 2.45-2.55 (2H, m), 3.91 (2H, s), 7.34 (2H, d, J=8.1), 7.47 (2H,d, J=8.1), 7.51-7.62 (2H, m), 7.72-7.82 (1H, m), 7.92 (1H, d, J=7.8),11.75 (1H, br)

379b)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-4-yloxy)pyrimidin-4(3H)-one

To a solution of4′-[(1-hydroxy-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.41 g), tetrahydro-4-pyranol (0.35 g) and triphenylphosphine (0.91 g)in tetrahydrofuran (4 mL) was added diisopropyl azodicarboxylate (1.8mL, 1.9 M toluene solution), and the mixture was stirred at roomtemperature for 12 hr. The reaction mixture was diluted with ethylacetate, washed with 1 M hydrochloric acid and then with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was crudely purified bysilica gel column chromatography. The crudely purified product wasdissolved in dimethyl sulfoxide (10 mL), hydroxylammonium chloride (1.4g), sodium hydrogen carbonate (1.9 g) was added, and the mixture wasstirred at 90° C. for 24 hr. The mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and theprecipitated solid was collected by filtration. The obtained solid wasdissolved in ethyl acetate. The solution was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.28 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.29 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.2), 1.39-1.56 (2H, m),1.58-1.75 (2H, m), 1.84-1.96 (2H, m), 2.40-2.53 (5H, m), 3.27-3.40 (2H,m), 3.83-3.95 (4H, m), 4.56-4.69 (1H, m), 7.18-7.27 (4H, m), 7.46-7.57(2H, m), 7.61-7.71 (2H, m), 12.38 (1H, br)

Example 380

2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[4-(tetrahydro-2H-pyran-4-ylmethoxy)phenyl]pyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.5 g), tetrahydropyranyl-4-methanol (0.26 g) and triphenylphosphine(0.58 g) in tetrahydrofuran (5 mL) was added diisopropylazodicarboxylate (1.2 mL, 1.9 M toluene solution), and the mixture wasstirred at room temperature for 12 hr. The reaction mixture was dilutedwith ethyl acetate, washed with 1 M hydrochloric acid and then withsaturated brine, and dried over anhydrous sodium sulfate. The solventwas evaporated under reduced pressure. The residue was crudely purifiedby silica gel column chromatography. The crudely purified product wasdissolved in dimethyl sulfoxide (10 mL), hydroxylammonium chloride (1.0g), sodium hydrogen carbonate (1.5 g) was added, and the mixture wasstirred at 90° C. for 24 hr. The mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and theprecipitated solid was collected by filtration. The obtained solid wasdissolved in ethyl acetate. The solution was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.21 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.49 g, 73%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.04 (3H, t, J=7.2),1.25-1.45 (2H, m), 1.49-1.65 (2H, m), 1.65-1.76 (2H, m), 1.94-2.11 (1H,m), 2.27 (2H, q, J=7.2), 2.46-2.58 (2H, m), 3.26-3.41 (2H, m), 3.83-3.94(6H, m), 7.05 (2H, d, J=8.7), 7.16-7.31 (6H, m), 7.44-7.58 (2H, m),7.60-7.72 (2H, m), 12.39 (1H, br)

Example 3812-ethyl-3-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

381a)4′-{[2-ethyl-1-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.99 g) in N,N-dimethylacetamide (10 mL) were added6-oxabicyclo[3.1.0]hexane (0.56 g) and cesium carbonate (1.4 g), and themixture was stirred at 120° C. for 24 hr. The mixture was allowed tocool to room temperature. The insoluble material was filtered off,diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturatedsodium hydrogen carbonate and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel chromatography to give the titlecompound (0.59 g, 50%) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.14 (3H, t, J=7.2),1.62-1.90 (6H, m), 2.00-2.25 (2H, m), 2.38 (2H, q, J=7.2), 2.61-2.72(2H, m), 3.96 (2H, s), 4.26-4.36 (1H, br), 4.48-4.59 (1H, br), 6.96-7.16(4H, m), 7.36-7.51 (6H, m), 7.57-7.66 (1H, m), 7.74 (1H, d, J=7.8)

381b)2-ethyl-3-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (1.9 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-ethyl-1-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.59 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.18 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.29 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.48-1.95 (7H, m), 2.05-2.20 (1H, m), 2.28 (2H, q, J=7.2), 2.46-2.59(2H, m), 3.86 (2H, s), 4.08 (1H, br), 4.49 (1H, br), 5.02 (1H, d,J=3.9), 7.01-7.09 (2H, m), 7.17-7.30 (6H, m), 7.44-7.56 (2H, m),7.60-7.69 (2H, m), 12.42 (1H, br)

Example 382

2-ethyl-3-{4-[(2-oxocyclopentyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of2-ethyl-3-(4-{[(2R)-2-hydroxycyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.2 g) in dichloromethane (4 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.22 g),and the mixture was stirred for 2 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.13 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.49-1.66 (2H, m), 1.75-2.04 (3H, m), 2.22-2.37 (4H, m), 2.44-2.59 (3H,m), 3.87 (2H, s), 5.00 (1H, d, J=9.6), 7.10 (2H, d, J=8.4), 7.17-7.32(6H, m), 7.45-7.59 (2H, m), 7.60-7.73 (2H, m), 12.39 (1H, br)

Example 3833-{[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

383a)4′-[(1-{[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(1-hydroxy-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.50 g), (2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (0.54 g) andtriphenylphosphine (1.1 g) in tetrahydrofuran (5 mL) was addeddiisopropyl azodicarboxylate (2.2 mL, 1.9 M toluene solution), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.62 g, 95%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (3H, t, J=7.2), 1.07-1.30 (6H, m),1.39-1.53 (2H, m), 1.87-1.97 (2H, m), 1.99-2.10 (2H, m), 2.48-2.59 (5H,m), 3.38-3.53 (2H, m), 3.95 (2H, s), 3.98-4.14 (1H, m), 7.30-7.51 (6H,m), 7.56-7.66 (1H, m), 7.74 (1H, d, J=8.1)

383b)3-{[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.2 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-[(1-{[(2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.62 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.32 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.29 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.25 g, 35%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.2), 1.09 (6H, d, J=6.6),1.26-1.41 (2H, m), 1.41-1.56 (2H, m), 1.86-1.98 (2H, m), 2.40-2.53 (5H,m), 3.85 (2H, s), 3.87-4.01 (2H, m), 4.60 (1H, br), 7.15-7.29 (4H, m),7.45-7.58 (2H, m), 7.61-7.72 (2H, m), 12.37 (1H, br)

Example 3842-ethyl-3-(4-{[(1R,2R)-2-hydroxycyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

384a)4′-{[2-ethyl-1-(4-{[(1R,2R)-2-hydroxycyclohexyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) in N,N-dimethylacetamide (20 mL) were added7-oxabicyclo[4.1.0]heptane (0.66 g) and cesium carbonate (1.5 g), andthe mixture was stirred at 120° C. for 24 hr. The mixture was allowed tocool to room temperature. The insoluble material was filtered off,diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturatedsodium hydrogen carbonate and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography to give the titlecompound (0.76 g, 62%) as a pale-yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.15 (3H, t, J=7.2),1.24-1.48 (4H, m), 1.63-1.83 (4H, m), 2.07-2.23 (2H, m), 2.31-2.44 (2H,m), 2.38 (2H, q, J=7.2), 2.51 (1H, br), 2.61-2.72 (2H, m), 3.67-3.80(1H, m), 3.96 (2H, s), 3.98-4.10 (1H, m), 7.00-7.17 (4H, m), 7.35-7.51(6H, m), 7.56-7.66 (1H, m), 7.74 (1H, d, J=7.8)

384b)2-ethyl-3-(4-{[(1R,2R)-2-hydroxycyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-{[2-ethyl-1-(4-{[(1R,2R)-2-hydroxycyclohexyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.76 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.22 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.46 g, 55%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.23-1.43 (4H, m), 1.47-1.68 (4H, m), 1.80-1.94 (1H, m), 2.00-2.09 (1H,m), 2.29 (2H, q, J=7.2), 2.49-2.58 (2H, m), 3.46-3.61 (1H, m), 2.86 (2H,s), 4.04-4.15 (1H, m), 4.93 (1H, d, J=4.5), 7.02-7.13 (2H, m), 7.16-7.31(6H, m), 7.46-7.59 (2H, m), 7.60-7.73 (2H, m), 12.38 (1H, br)

Example 3856-butyl-2-ethyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

385a) [2-(4-bromophenoxy)-2-methylpropoxy](tert-butyl)dimethylsilane

To a solution of 2-(4-bromophenoxy)-2-methylpropan-1-ol (25.4 g) and2,6-lutidine (30.2 mL) in dichloromethane (300 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (28.6 mL) underice-cooling, and the mixture was stirred for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless oil (37.1 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.07 (6H, s), 0.92 (9H, s), 1.25 (6H, s), 5.53(2H, s), 6.90 (2H, d, J=8.7), 7.35 (2H, d, J=8.7)

385b)tert-butyl(dimethyl){2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propoxy}silane

To a solution of[2-(4-bromophenoxy)-2-methylpropoxy](tert-butyl)dimethylsilane (33.8 g),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (28.7 g),potassium acetate (27.7 g) in N,N-dimethylformamide (400 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (2.3 g), and themixture was stirred at 90° C. for 12 hr under an argon atmosphere. Thereaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography to give the title compoundas a pale-yellow oil (27.3 g, 71%).

¹H NMR (300 MHz, CDCl₃) δ 0.07 (6H, s), 0.92 (9H, s), 1.28 (6H, s), 1.34(12H, s), 3.56 (2H, s), 7.01 (2H, d, J=8.7), 7.71 (2H, d, J=8.7)

385c) {4-[2-(acetyloxy)-1,1-dimethylethoxy]phenyl}boronic acid

A solution oftert-butyl(dimethyl){2-methyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propoxy}silane(5.0 g) in acetic acid (30 mL)-tetrahydrofuran (10 mL)-water (10 mL) wasstirred for 2 days. The reaction mixture was diluted with toluene andthe solvent was evaporated under reduced pressure. The residue wasdissolved in ethyl acetate, washed with saturated aqueous sodiumhydrogen carbonate solution and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in dichloromethane (20 mL), pyridine(2.4 mL), acetic anhydride (1.5 g) and N,N-dimethyl-4-aminopyridine (0.1g) were added and the mixture was stirred for 2 hr. Small pieces of icewere added to the reaction mixture, and the mixture was stirred for 30min, extracted with ethyl acetate, washed with 1 M hydrochloric acid,saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved in 1 Mhydrochloric acid (10 mL)-tetrahydrofuran (10 mL)-water (10 mL), sodiumperiodate (3.2 g) was added, and the mixture was stirred at roomtemperature for 3 hr. The reaction mixture was diluted with water,extracted with ethyl acetate, washed with 1 M hydrochloric acid,saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was triturated withdiisopropyl ether to give the title compound as a pale-yellow solid (1.6g, 52%).

¹H NMR (300 MHz, CDCl₃) δ 1.28 (6H, s), 2.09 (3H, s), 4.04 (2H, s), 6.97(2H, d, J=7.8), 7.79 (2H, d, J=7.8)

385d)2-{4-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxopyrimidin-1(6H)-yl]phenoxy}-2-methylpropylacetate

To a suspension of4′-[(4-butyl-2-ethyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), {4-[2-(acetyloxy)-1,1-dimethylethoxy]phenyl}boronic acid (0.68g), triethylamine (0.96 mL), pyridine (0.56 mL) and molecular sieves 4 A(1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.68 g)and the mixture was stirred for 2 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.6 g, 76%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (3H, t, J=7.2), 1.14 (3H, t, J=7.2), 1.36(6H, s), 1.37-1.46 (2H, m), 1.59-1.71 (2H, m), 2.15 (3H, s), 2.35 (2H,q, J=7.2), 2.63-2.73 (2H, m), 3.97 (2H, s), 4.15 (2H, s), 7.14 (4H, s),7.37-7.52 (6H, m), 7.58-7.66 (1H, m), 7.74 (1H, d, J=7.5)

385e)6-butyl-2-ethyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of2-{4-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxopyrimidin-1(6H)-yl]phenoxy}-2-methylpropylacetate (0.6 g) in methanol (4 mL)-tetrahydrofuran (4 mL) was addedpotassium carbonate (0.29 g), and the mixture was stirred for 1 hr. 1 Mhydrochloric acid was added to the reaction mixture, and the mixture wasextracted with ethyl acetate, washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in dichloromethane (10 mL),2,6-lutidine (0.3 mL) and tert-butyl(dimethyl)silyltrifluoromethanesulfonate (0.36 mL) were added under ice-cooling, andthe mixture was stirred for 1 hr. The reaction mixture was diluted withethyl acetate, washed with 1 M hydrochloric acid and then with saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved in dimethylsulfoxide (8 mL), hydroxylammonium chloride (1.2 g) and sodium hydrogencarbonate (1.8 g) were added, and the mixture was stirred at 90° C. for24 hr. The mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (6 mL), tetrabutylammonium fluoride (2.4 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was stirred for 2hr. The reaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and saturated brine, and dried over anhydrous sodiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.28 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.25 (6H, s), 1.27-1.40 (2H, m), 1.45-1.59 (2H, m), 2.28 (2H, q, J=7.2),2.52-2.60 (2H, m), 3.41 (2H, d, J=4.5), 3.86 (2H, s), 4.90-4.98 (1H, m),7.13 (2H, d, J=8.7), 7.18-7.31 (6H, m), 7.47-7.58 (2H, m), 7.62-7.73(2H, m), 12.39 (1H, br)

Example 386

2-ethyl-3-{4-[(2-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of2-ethyl-3-(4-{[(1R,2R)-2-hydroxycyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.2 g) in dichloromethane (5 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.21 g),and the mixture was stirred for 2 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.13 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.48-1.67 (3H, m), 1.73-1.93 (3H, m), 2.21-2.43 (5H, m), 2.51-2.58 (2H,m), 2.58-2.75 (1H, m), 3.86 (2H, s), 5.04-5.15 (1H, m), 6.97 (2H, d,J=7.8), 7.16-7.32 (6H, m), 7.45-7.58 (2H, m), 7.60-7.72 (2H, m), 12.39(1H, br)

Example 3872-ethyl-3-(4-{[4-(hydroxymethyl)cyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

387a) ethyl4-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}cyclohexanecarboxylate

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.50 g), ethyl 4-hydroxycyclohexanecarboxylate (1.7 g) andtriphenylphosphine (2.6 g) in tetrahydrofuran (15 mL) was addeddiisopropyl azodicarboxylate (5.3 mL, 1.9 M toluene solution), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (1.78 g, 88%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.14 (3H, t, J=7.2),1.20-1.32 (5H, m), 1.43-1.82 (4H, m), 1.91-2.27 (4H, m), 2.32-2.45 (3H,m), 2.61-2.72 (2H, m), 3.96 (2H, s), 4.08-4.30 (3H, m), 6.95-7.04 (2H,m), 7.11 (2H, d, J=9.0), 7.36-7.51 (6H, m), 7.57-7.65 (1H, m), 7.74 (1H,d, J=7.8)

387b)4′-{[2-ethyl-1-(4-{[4-(hydroxymethyl)cyclohexyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of sodium borohydride (0.85 g) in ethanol (10mL)-tetrahydrofuran (10 mL) was added calcium chloride (1.3 g) underice-cooling, and the mixture was stirred for 15 min. A solution of ethyl4-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}cyclohexanecarboxylate(1.7 g) in tetrahydrofuran (10 mL) was added, and the mixture wasfurther stirred for 2 hr. Small pieces of ice were added in the reactionmixture and the mixture was stirred for 15 min and diluted with ethylacetate and 1 M hydrochloric acid. The organic layer was separated,washed with saturated sodium hydrogen carbonate and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel chromatographyto give the title compound (1.1 g, 71%) as a solid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.10-1.19 (4H, m),1.30-1.64 (5H, m), 1.64-1.79 (2H, m), 1.85-1.98 (1H, m), 2.02-2.12 (1H,m), 2.14-2.27 (1H, m), 2.39 (2H, q, J=7.2), 2.62-2.72 (2H, m), 3.45-3.56(2H, br), 3.96 (2H, s), 4.13-4.25 (1H, m), 4.58 (1H, br), 6.95-7.04 (2H,m), 7.06-7.15 (2H, m), 7.36-7.52 (6H, m), 7.57-7.65 (1H, m), 7.73 (1H,d, J=7.8)

387c)2-ethyl-3-(4-{[4-(hydroxymethyl)cyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-{[4-(hydroxymethyl)cyclohexyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.4 g) and 2,6-lutidine (0.25 mL) in dichloromethane (6 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.33 mL) underice-cooling, and the mixture was stirred for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin dimethyl sulfoxide (6 mL), hydroxylammonium chloride (0.85 g) andsodium hydrogen carbonate (1.2 g) were added, and the mixture wasstirred at 90° C. for 24 hr. The mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and theprecipitated solid was collected by filtration. The obtained solid wasdissolved in ethyl acetate. The solution was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (8 mL).N,N′-carbonyldiimidazole (0.17 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (5 mL), tetrabutylammonium fluoride (1.6 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was stirred for 2hr. The reaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.26 g, 77%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 0.98-1.22 (6H, m),1.26-1.67 (6H, m), 1.72-7.92 (2H, m), 2.04-2.18 (1H, m), 2.29 (2H, q,J=7.2), 2.50-2.60 (2H, m), 3.19-3.30 (2H, m), 3.87 (2H, s), 4.23-4.37(1H, m), 7.04 (2H, d, J=9.0), 7.17-7.32 (6H, m), 7.46-7.58 (2H, m),7.61-7.72 (1H, m), 12.38 (1H, br)

Example 388

3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-2-methoxy-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methoxy-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g), (2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (0.43 g) andtriphenylphosphine (0.87 g) in tetrahydrofuran (5 mL) was addeddiisopropyl azodicarboxylate (1.75 mL, 1.9 M toluene solution), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wascrudely purified by silica gel column chromatography. The crudelypurified product was dissolved in dimethyl sulfoxide (10 mL),hydroxylammonium chloride (1.3 g) and sodium hydrogen carbonate (1.9 g)were added, and the mixture was stirred at 90° C. for 24 hr. The mixturewas allowed to cool to room temperature, water was added to the reactionmixture, and the precipitated solid was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated and the residue was dissolved in tetrahydrofuran(10 mL). N,N′-carbonyldiimidazole (0.27 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.21 g, 31%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.09 (6H, d, J=6.0),1.34-1.48 (2H, m), 1.50-1.66 (2H, m), 1.78-1.91 (2H, m), 2.45-2.55 (2H,m), 3.75-3.91 (7H, m), 4.81 (1H, s), 7.01 (2H, d, J=9.0), 7.16-7.31 (6H,m), 7.45-7.58 (2H, m), 7.60-7.72 (2H, m), 12.33 (1H, br)

Example 3892-ethyl-3-(4-{[1-(methoxymethyl)cyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

389a) methyl1-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}cyclopentanecarboxylate

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) in N,N-dimethylacetamide (10 mL) were added methyl1-bromocyclopentanecarboxylate (1.4 g) and cesium carbonate (2.2 g), andthe mixture was stirred at 120° C. for 24 hr. The mixture was allowed tocool to room temperature. The insoluble material was filtered off,diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturatedsodium hydrogen carbonate and saturated brine, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography to give the titlecompound (0.94 g, 77%) as a pale-yellow solid.

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.4), 1.13 (3H, t, J=7.4),1.63-1.90 (6H, m), 2.15-2.41 (6H, m), 2.62-2.70 (2H, m), 3.75 (3H, s),3.96 (2H, s), 6.80-6.88 (2H, m), 7.02-7.11 (2H, m), 7.35-7.51 (6H, m),7.57-7.65 (1H, m), 7.74 (1H, d, J=7.6)

389b)4′-{[2-ethyl-1-(4-{[1-(hydroxymethyl)cyclopentyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of sodium borohydride (0.39 g) in methanol (10mL)-tetrahydrofuran (10 mL) was added calcium chloride (0.57 g) underice-cooling, and the mixture was stirred for 15 min. A solution ofmethyl1-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}cyclopentanecarboxylate(0.94 g) in tetrahydrofuran (10 mL) was added, and the mixture wasfurther stirred for 2 hr. Small pieces of ice were added in the reactionmixture and the mixture was stirred for 15 min. The mixture was dilutedwith ethyl acetate and 1 M hydrochloric acid. The organic layer wasseparated, washed with saturated sodium hydrogen carbonate and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound (0.83 g, 93%) as acolorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.15 (3H, t, J=7.2),1.61-1.88 (8H, m), 1.95-2.14 (3H, m), 2.37 (2H, q, J=7.2), 2.61-2.72(2H, m), 3.77 (2H, d, J=5.4), 3.97 (2H, s), 7.06-7.15 (4H, m), 7.37-7.50(6H, m), 7.58-7.65 (1H, m), 7.74 (1H, d, J=7.8)

389c)2-ethyl-3-(4-{[1-(methoxymethyl)cyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-{[1-(hydroxymethyl)cyclopentyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.41 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.06g, 60%), and the mixture was stirred for 15 min. Then methyl iodide(0.09 mL) was added, and the mixture was further stirred for 2 hr. Smallpieces of ice were added to the reaction mixture and the mixture wasstirred for 15 min. The reaction mixture was diluted with ethyl acetate,washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas dissolved in dimethyl sulfoxide (5 mL), hydroxylammonium chloride(0.91 g) and sodium hydrogen carbonate (1.3 g) were added, and themixture was stirred at 90° C. for 24 hr. The mixture was allowed to coolto room temperature, water was added to the reaction mixture, and theprecipitated solid was collected by filtration. The obtained solid wasdissolved in ethyl acetate. The solution was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (6 mL).N,N′-carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel chromatography to give the title compound (0.17 g, 36%) asa colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.5),1.49-2.00 (10H, m), 2.28 (2H, q, J=7.2), 2.51-2.58 (2H, m), 3.28 (3H,s), 3.55 (2H, s), 3.87 (2H, s), 7.07 (2H, d, J=8.7), 7.18-7.31 (6H, m),7.46-7.58 (2H, m), 7.61-7.72 (2H, m), 12.38 (1H, s)

Example 390

2-ethyl-3-(4-{[1-(hydroxymethyl)cyclopentyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-{[1-(hydroxymethyl)cyclopentyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.42 g) and 2,6-lutidine (0.27 mL) in dichloromethane (10 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.35 mL) underice-cooling, and the mixture was stirred for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin dimethyl sulfoxide (5 mL), hydroxylammonium chloride (0.91 g) andsodium hydrogen carbonate (1.3 g) were added, and the mixture wasstirred at 90° C. for 24 hr. The mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and theprecipitated solid was collected by filtration. The obtained solid wasdissolved in ethyl acetate. The solution was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (6 mL).N,N′-carbonyldiimidazole (0.19 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (5 mL), tetrabutylammonium fluoride (4 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was stirred for 2hr. The reaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.27 g, 58%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.49-1.96 (10H, m), 2.8 (2H, q, J=7.2), 2.50-2.59 (2H, m), 3.61 (2H, d,J=4.8), 3.86 (2H, s), 4.97 (1H, t, J=4.8), 7.08 (2H, d, J=8.7),7.16-7.32 (6H, m), 7.45-7.58 (2H, m), 7.60-7.73 (2H, m), 12.38 (1H, br)

Example 391

2-ethyl-3-{4-[(4-hydroxy-4-methylcyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g), 1-methylcyclohexane-1,4-diol (0.43 g) and triphenylphosphine(0.88 g) in tetrahydrofuran (3 mL) was added diisopropylazodicarboxylate (1.8 mL, 1.9 M toluene solution), and the mixture wasstirred for 1 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was crudely purifiedby silica gel column chromatography. The crudely purified product wasdissolved in dimethyl sulfoxide (6 mL), hydroxylammonium chloride (0.76g) and sodium hydrogen carbonate (1.1 g) were added, and the mixture wasstirred at 90° C. for 24 hr. The mixture was allowed to cool to roomtemperature, water was added to the reaction mixture, and theprecipitated solid was collected by filtration. The obtained solid wasdissolved in ethyl acetate. The solution was washed with saturated brineand dried over anhydrous sodium sulfate. The solvent was evaporated andthe residue was dissolved in tetrahydrofuran (6 mL).N,N′-carbonyldiimidazole (0.10 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.13 g, 19%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.16 (3H, s), 1.35-1.71 (8H, m), 1.84-2.03 (2H, m), 2.28 (2H, q, J=7.2),2.44-2.59 (2H, m), 3.86 (2H, s), 4.20 (1H, s), 4.48-4.60 (1H, m), 7.05(2H, d, J=9.3), 7.17-7.31 (6H, m), 7.46-7.59 (2H, m), 7.60-7.74 (2H, m),12.39 (1H, br)

Example 3922-ethyl-3-(4-{[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

392a)4′-{[1-(4-{[trans-4-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)cyclohexyl]oxy}phenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.58 g),cis-4-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)cyclohexanol(1.05 g) and triphenylphosphine (1.01 g) in tetrahydrofuran (10 mL) wasadded diisopropyl azodicarboxylate (2.0 mL, 1.9 M toluene solution), andthe mixture was stirred for 1 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (0.49 g, 54%).

¹H NMR (300 MHz, CDCl₃) δ 0.07 (6H, s), 0.86 (6H, s), 0.87 (9H, s), 1.01(3H, t, J=7.2), 1.10-1.28 (6H, m), 1.30-1.50 (2H, m), 1.63-1.79 (2H, m),1.79-1.97 (2H, m), 2.14-2.28 (2H, m), 2.38 (2H, q, J=7.2), 2.62-2.72(2H, m), 3.97 (2H, s), 4.05-4.20 (1H, m), 6.99 (2H, d, J=9.0), 7.08 (2H,d, J=9.0), 7.36-7.52 (6H, m), 7.56-7.66 (1H, m), 7.74 (1H, d, J=6.9)

392b)2-ethyl-3-(4-{[trans-4-(1-hydroxy-1-methylethyl)cyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.82 g), sodium hydrogencarbonate (1.2 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[1-(4-{[trans-4-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)cyclohexyl]oxy}phenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.48 g) was added, and the mixture was stirred at 90° C. for 8 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.17 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin 1,4-dioxane (5 mL), tetrabutylammonium fluoride (2.1 mL, 1.0 Mtetrahydrofuran solution) was added and the mixture was heated underreflux for 24 hr. The reaction mixture was diluted with ethyl acetate,washed with 1 M hydrochloric acid and saturated brine, and dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound as a colorless solid (0.094 g, 21%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.5), 0.99-1.09 (9H, m),1.13-1.40 (4H, m), 1.42-1.65 (3H, m), 1.78-1.91 (2H, m), 2.08-2.20 (2H,m), 2.28 (2H, q, J=7.2), 2.49-2.58 (2H, m), 3.86 (2H, s), 4.09 (1H, s),4.21-4.35 (1H, m), 7.04 (2H, d, J=9.0), 7.16-7.30 (6H, m), 7.43-7.56(2H, m), 7.58-7.70 (2H, m)

Example 3932-ethyl-3-(4-morpholin-4-ylphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

393a)4′-{[2-ethyl-1-(4-morpholin-4-ylphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), (4-morpholin-4-ylphenyl)boronic acid (0.58 g), triethylamine(0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) indichloromethane (10 mL) was added copper(II) acetate (0.51 g) and themixture was stirred for 2 days. The reaction mixture was diluted withethyl acetate, the insoluble material was filtered off through celite,and the filtrate was concentrated. The residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (0.53 g, 73%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.14 (3H, t, J=7.2),1.64-1.79 (2H, m), 2.19 (2H, q, J=7.2), 2.62-2.72 (2H, m), 3.21 (4H, t,J=4.8), 3.87 (4H, t, J=4.8), 3.96 (2H, s), 6.99 (2H, d, J=9.0), 7.10(2H, d, J=9.0), 7.36-7.51 (6H, m), 7.57-7.65 (1H, m), 7.73 (1H, d,J=6.3)

393b)2-ethyl-3-(4-morpholin-4-ylphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-{[2-ethyl-1-(4-morpholin-4-ylphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.53 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.32 g, 54%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.48-1.67 (2H, m), 2.29 (2H, q, J=7.2), 2.45-2.58 (2H, m), 3.12-3.24(4H, m), 3.69-3.81 (4H, m), 3.86 (2H, s), 7.04 (2H, d, J=9.0), 7.11-7.32(6H, m), 7.45-7.60 (2H, m), 7.61-7.73 (2H, m), 12.38 (1H, br)

Example 394

2-ethyl-3-(4-{[cis-4-(1-hydroxy-1-methylethyl)cyclohexyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g),trans-4-(1-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)cyclohexanol(0.91 g) and triphenylphosphine (0.88 g) in tetrahydrofuran (5 mL) wasadded diisopropyl azodicarboxylate (1.8 mL, 1.9 M toluene solution), andthe mixture was stirred for 1 hr. Ethyl acetate and water were added tothe reaction mixture, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas crudely purified by silica gel column chromatography. The crudelypurified product was dissolved in dimethyl sulfoxide (10 mL),hydroxylammonium chloride (1.3 g) and sodium hydrogen carbonate (1.9 g)were added, and the mixture was stirred at 90° C. for 24 hr. The mixturewas allowed to cool to room temperature, water was added to the reactionmixture, and the precipitated solid was collected by filtration. Theobtained solid was dissolved in ethyl acetate. The solution was washedwith saturated brine and dried over anhydrous sodium sulfate. Thesolvent was evaporated and the residue was dissolved in tetrahydrofuran(10 mL). N,N′-carbonyldiimidazole (0.27 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin 1,4-dioxane (5 mL), tetrabutylammonium fluoride (2.1 mL, 1.0 Mtetrahydrofuran solution) was added, and the mixture was heated underreflux for 24 hr. The reaction mixture was diluted with ethyl acetate,washed with 1 M hydrochloric acid and saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.16 g,23%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 0.96-1.11 (9H, m),1.22-1.69 (9H, m), 1.92-2.09 (2H, m), 2.29 (2H, q, J=7.2), 2.44-2.62(2H, m), 3.86 (2H, s), 4.02-4.07 (1H, m), 4.65 (1H, s), 7.04 (2H, d,J=9.0), 7.16-7.31 (6H, m), 7.44-7.58 (2H, m), 7.60-7.72 (2H, m), 12.38(1H, br)

Example 395

3-{4-[2-ethoxy-1-(ethoxymethyl)ethoxy]phenyl}-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g), 1,3-diethoxypropan-2-ol (0.49 g) and triphenylphosphine (0.88g) in tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate (1.8mL, 1.9 M toluene solution), and the mixture was stirred for 1 hr. Ethylacetate and water were added to the reaction mixture, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was crudely purified by silica gel columnchromatography. The crudely purified product was dissolved in dimethylsulfoxide (10 mL), hydroxylammonium chloride (1.3 g) and sodium hydrogencarbonate (1.9 g) were added, and the mixture was stirred at 90° C. for24 hr. The mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.42 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 0.99-1.14 (9H, m),1.49-1.66 (2H, m), 2.29 (2H, q, J=7.2), 2.50-2.58 (2H, m), 3.48 (4H, q,J=7.2), 3.54-3.67 (4H, m), 3.87 (2H, s), 4.58-4.68 (1H, m), 7.10 (2H, d,J=9.0), 7.17-7.38 (6H, m), 7.46-7.58 (2H, m), 7.60-7.72 (2H, m), 12.39(1H, br)

Example 3965-{[3-chloro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one

396a)3′-chloro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a suspension of 60% sodium hydride (0.40 g) in tetrahydrofuran (20mL) was added dropwise a solution of ethyl butyrylacetate (2.13 g) intetrahydrofuran (10 mL). After stirring for 30 min,4′-(bromomethyl)-3′-chlorobiphenyl-2-carbonitrile (2.06 g) was added.The mixture was stirred at room temperature for 15 hr, and 1 Mhydrochloric acid was added. The mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography to give ethyl2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate. Then, asolution of the obtained ethyl2-[(3-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate,ethanimidamide hydrochloride (2.55 g), 28% sodium methoxide (7.80 g) inmethanol (50 mL) was stirred overnight. The solvent was evaporated underreduced pressure, and saturated aqueous ammonium chloride solution wasadded to the residue. The precipitated solid was collected byfiltration, and washed with water and diethyl ether to give the titlecompound (0.64 g, 73%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 0.93 (t, J=7.5, 3H), 1.48-1.66 (m, 2H), 2.42(s, 3H), 2.45-2.54 (m, 2H), 4.06 (s, 2H), 7.13 (d, J=8.1, 1H), 7.30-7.36(m, 1H), 7.40-7.50 (m, 2H), 7.56 (d, J=2.1, 1H), 7.59-7.66 (m, 1H),7.71-7.77 (m, 1H)

396b)5-{[3-chloro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one

To a suspension of3′-chloro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.65 g), (4-isopropoxyphenyl)boronic acid (0.62 g), triethylamine (0.8mL), pyridine (1.6 mL) and molecular sieves 4 A (1.60 g) indichloromethane (20 mL) was added copper(II) acetate (0.65 g) and themixture was stirred at room temperature for 2 days. The reaction mixturewas diluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography. The crudely purifiedproduct was added to a mixture of hydroxylammonium chloride (1.30 g),sodium hydrogen carbonate (2.10 g) and dimethyl sulfoxide (25 mL), whichhad been stirred at 40° C. for 30 min, and the mixture was stirred at90° C. for 18 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was dissolved in tetrahydrofuran (20 mL).N,N′-carbonyldiimidazole (0.31 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.57 g, 58%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.2, 3H), 1.35 (d, J=6.3, 6H),1.53-1.80 (m, 2H), 2.17 (s, 3H), 2.60-2.70 (m, 2H), 3.99 (s, 2H),4.48-4.62 (m, 1H), 6.87-7.10 (m, 6H), 7.34-7.50 (m, 3H), 7.54-7.62 (m,1H), 7.68-7.75 (m, 1H)

Example 397

5-{[3-chloro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-propylpyrimidin-4(3H)-one

To a suspension of3′-chloro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.65 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.66g), triethylamine (0.8 mL), pyridine (1.6 mL) and molecular sieves 4 A(1.60 g) in dichloromethane (20 mL) was added copper(II) acetate (0.65g) and the mixture was stirred at room temperature for 2 days. Thereaction mixture was diluted with ethyl acetate, the insoluble materialwas filtered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography. The crudelypurified product was added to a mixture of hydroxylammonium chloride(1.38 g), sodium hydrogen carbonate (2.22 g) and dimethyl sulfoxide (20mL), which had been stirred at 40° C. for 30 min, and the mixture wasstirred at 90° C. for 18 hr. The reaction mixture was allowed to cool toroom temperature, ethyl acetate and water were added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was dissolved in tetrahydrofuran (20 mL).N,N′-carbonyldiimidazole (0.33 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.68 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.2, 3H), 1.47 (s, 3H), 1.49 (s,3H), 1.54-1.80 (m, 2H), 2.19 (s, 3H), 2.54-2.72 (m, 2H), 3.02 (s, 2H),3.99 (s, 2H), 6.68 (d, J=8.1, 1H), 6.77-7.10 (m, 4H), 7.32-7.50 (m, 3H),7.54-7.62 (m, 1H), 7.66-7.75 (m, 1H)

Example 3985-{[2-chloro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one

398a)2′-chloro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a suspension of 60% sodium hydride (0.50 g) in tetrahydrofuran (20mL) was added dropwise a solution of ethyl butyrylacetate (2.40 g) intetrahydrofuran (10 mL). After stirring for 30 min,4′-(bromomethyl)-2′-chlorobiphenyl-2-carbonitrile (2.30 g) was added.The mixture was stirred at room temperature for 15 hr, and 1 Mhydrochloric acid was added. The mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography to give ethyl2-[(2-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate. Then, asolution of the obtained ethyl2-[(2-chloro-2′-cyanobiphenyl-4-yl)methyl]-3-oxohexanoate,ethanimidamide hydrochloride (1.35 g) and 28% sodium methoxide (4.09 g)in methanol (30 mL) was stirred overnight. The solvent was evaporatedunder reduced pressure, and saturated aqueous ammonium chloride solutionwas added to the residue. The precipitated solid was collected byfiltration, and washed with water and diethyl ether to give the titlecompound (1.95 g, 73%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.5, 3H), 1.52-1.72 (m, 2H), 2.43(s, 3H), 2.54-2.64 (m, 2H), 3.93 (s, 2H), 7.20-7.28 (m, 2H), 7.37-7.50(m, 3H), 7.58-7.65 (m, 1H), 7.71-7.76 (m, 1H), 12.32 (s, 1H)

398b)5-{[2-chloro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one

To a suspension of2′-chloro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.65 g), (4-isopropoxyphenyl)boronic acid (0.62 g), triethylamine (0.8mL), pyridine (1.6 mL) and molecular sieves 4 A (1.60 g) indichloromethane (20 mL) was added copper(II) acetate (0.65 g) and themixture was stirred at room temperature for 2 days. The reaction mixturewas diluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography. The crudely purifiedproduct was added to a mixture of hydroxylammonium chloride (1.42 g),sodium hydrogen carbonate (2.30 g) and dimethyl sulfoxide (20 mL), whichhad been stirred at 40° C. for 30 min, and the mixture was stirred at90° C. for 18 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was dissolved in tetrahydrofuran (20 mL).N,N′-carbonyldiimidazole (0.33 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.31 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.75 g, 78%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.2, 3H), 1.35 (d, J=6.0, 6H),1.53-1.80 (m, 2H), 2.17 (s, 3H), 2.64-2.74 (m, 2H), 3.89 (s, 2H),4.48-4.60 (m, 1H), 6.88-6.97 (m, 2H), 7.02-7.10 (m, 2H), 7.14 (d, J=7.8,1H), 7.22-7.37 (m, 3H), 7.46-7.62 (m, 2H), 7.81 (d, J=7.8, 1H)

Example 399

5-{[2-chloro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-propylpyrimidin-4(3H)-one

To a suspension of2′-chloro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.65 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.66g), triethylamine (0.8 mL), pyridine (1.6 mL) and molecular sieves 4 A(1.60 g) in dichloromethane (20 mL) was added copper(II) acetate (0.65g) and the mixture was stirred at room temperature for 2 days. Thereaction mixture was diluted with ethyl acetate, the insoluble materialwas filtered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography. The crudelypurified product was added to a mixture of hydroxylammonium chloride(1.57 g), sodium hydrogen carbonate (2.53 g) and dimethyl sulfoxide (25mL), which had been stirred at 40° C. for 30 min, and the mixture wasstirred at 90° C. for 18 hr. The reaction mixture was allowed to cool toroom temperature, ethyl acetate and water were added, and the mixturewas extracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was dissolved in tetrahydrofuran (20 mL).N,N′-carbonyldiimidazole (0.37 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.34 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.75 g, 75%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.2, 3H), 1.47 (s, 3H), 1.50 (s,3H), 1.64-1.82 (m, 2H), 2.19 (s, 3H), 2.64-2.74 (m, 2H), 3.04 (s, 2H),3.89 (s, 2H), 6.73 (dd, J=8.1, 3.9, 1H), 6.82-6.96 (m, 2H), 7.10-7.38(m, 4H), 7.45-7.62 (m, 2H), 7.78-7.86 (m, 1H)

Example 4003-(4-isopropoxyphenyl)-5-{[2-methoxy-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

400a)2′-methoxy-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a suspension of 60% sodium hydride (1.80 g) in tetrahydrofuran (50mL) was added dropwise a solution of ethyl butyrylacetate (9.50 g) intetrahydrofuran (30 mL). After stirring for 30 min,4′-(bromomethyl)-2′-methoxybiphenyl-2-carbonitrile (8.79 g) was added.The mixture was stirred at room temperature for 15 hr, and 1 Mhydrochloric acid was added. The mixture was extracted with ethylacetate, and the organic layer was washed with saturated brine, driedover anhydrous magnesium sulfate and concentrated. The residue waspurified by silica gel column chromatography to give ethyl2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate. Then, asolution of the obtained ethyl2-[(2′-cyano-2-methoxybiphenyl-4-yl)methyl]-3-oxohexanoate,ethanimidamide hydrochloride (3.25 g) and 28% sodium methoxide (9.91 g)in methanol (70 mL) was stirred overnight. The solvent was evaporatedunder reduced pressure, and saturated aqueous ammonium chloride solutionwas added to the residue. The precipitated solid was collected byfiltration, and washed with water and diethyl ether to give the titlecompound (5.63 g, 52%) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.5, 3H), 1.54-1.72 (m, 2H), 2.41(s, 3H), 2.56-2.66 (m, 2H), 3.80 (s, 3H), 3.95 (s, 2H), 6.86-6.97 (m,2H), 7.09-7.15 (m, 1H), 7.34-7.44 (m, 2H), 7.54-7.62 (m, 1H), 7.66-7.72(m, 1H)

400b)3-(4-isopropoxyphenyl)-5-{[2-methoxy-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

To a suspension of2′-methoxy-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.00 g), (4-isopropoxyphenyl)boronic acid (1.00 g), triethylamine (1.3mL), pyridine (2.5 mL) and molecular sieves 4 A (2.50 g) indichloromethane (30 mL) was added copper(II) acetate (0.98 g) and themixture was stirred at room temperature for 2 days. The reaction mixturewas diluted with ethyl acetate, the insoluble material was filtered offthrough celite, and the filtrate was concentrated. The residue waspurified by silica gel column chromatography. The crudely purifiedproduct was added to a mixture of hydroxylammonium chloride (2.05 g),sodium hydrogen carbonate (3.31 g) and dimethyl sulfoxide (10 mL), whichhad been stirred at 40° C. for 30 min, and the mixture was stirred at90° C. for 18 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.48 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixturewas stirred at room temperature for 3 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas colorless crystals (0.88 g, 58%).

¹H NMR (300 MHz, CDCl₃) δ 1.05 (t, J=7.5, 3H), 1.36 (d, J=6.0, 6H),1.68-1.84 (m, 2H), 2.18 (s, 3H), 2.66-2.76 (m, 2H), 3.67 (s, 3H), 3.93(s, 2H), 4.48-4.64 (m, 1H), 6.92-7.02 (m, 4H), 7.05-7.12 (m, 3H),7.28-7.34 (m, 1H), 7.41-7.49 (m, 1H), 7.53-7.60 (m, 1H), 7.81-7.86 (m,1H)

Example 4015-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one

401a)2′-fluoro-4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of2′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (4-isopropoxyphenyl)boronic acid (0.51 g), copper acetate (0.5g), pyridine (1.1 mL), triethylamine (1.9 mL), molecular sieves 4 A (2.0g) and methylene chloride (10 mL) was stirred at room temperature for 24hr. Ethyl acetate was added to the reaction mixture, and the insolublesolid was filtered off. The solvent of the filtrate was evaporated underreduced pressure, and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.94 g, 69%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.4, 3H), 1.36 (d, J=6.0, 6H),1.63-1.79 (m, 2H), 2.19 (s, 3H), 2.59-2.69 (m, 2H), 3.95 (s, 2H),4.51-4.64 (m, 1H), 6.96-7.02 (m, 2H), 7.08-7.23 (m, 4H), 7.27-7.33 (m,1H), 7.41-7.50 (m, 2H), 7.59-7.66 (m, 1H), 7.75 (dd, J=8.01, 1.04, 1H)

401b)5-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.12 g), sodium hydrogencarbonate (1.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,2′-fluoro-4′-{[1-(4-isopropoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.94 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-carbonyldiimidazole (0.4 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.53 g,50%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.4, 3H), 1.30 (d, J=6.1, 6H),1.47-1.63 (m, 2H), 2.07 (s, 3H), 2.47-2.54 (m, 2H), 3.88 (s, 2H),4.59-4.74 (m, 1H), 7.00-7.17 (m, 4H), 7.20-7.31 (m, 3H), 7.44-7.53 (m,1H), 7.57-7.65 (m, 1H), 7.66-7.74 (m, 2H), 12.59 (s, 1H)

Example 4023-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

402a)4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile

A mixture of2′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(1.0 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.53g), copper acetate (0.5 g), pyridine (1.1 mL), triethylamine (1.9 mL),molecular sieves 4 A (2.0 g) and methylene chloride (10 mL) was stirredat room temperature for 24 hr. Ethyl acetate was added to the reactionmixture, and the insoluble solid was filtered off. The solvent of thefiltrate was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.98 g, 69%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.4, 3H), 1.50 (d, J=11, 6H),1.63-1.77 (m, 2H), 2.21 (s, 3H), 2.60-2.68 (m, 2H), 3.06 (d, J=2.6, 2H),3.95 (d, J=1.9, 2H), 6.79-6.84 (m, 1H), 6.89-7.00 (m, 2H), 7.10-7.22 (m,2H), 7.27-7.33 (m, 1H), 7.41-7.49 (m, 2H), 7.59-7.66 (m, 1H), 7.73-7.78(m, 1H)

402b)3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.14 g), sodium hydrogencarbonate (1.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[1-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}-2′-fluorobiphenyl-2-carbonitrile(0.98 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-carbonyldiimidazole (0.4 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.4 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as colorless crystals (0.6 g,55%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.2, 3H), 1.45 (d, J=3.8, 6H),1.49-1.61 (m, 2H), 2.09 (s, 3H), 2.45-2.58 (m, 2H), 3.05 (s, 2H), 3.88(s, 2H), 6.80 (d, J=8.3, 1H), 7.02-7.19 (m, 4H), 7.25 (t, J=8.0, 1H),7.48 (d, J=7.6, 1H), 7.57-7.64 (m, 1H), 7.65-7.74 (m, 2H), 12.59 (s, 1H)

Example 403

5-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-(4-isopropoxyphenyl)-2-methyl-6-propylpyrimidin-4(3H)-one(0.44 g) and ethanol (8 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.43 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.4, 3H), 1.30 (d, J=5.7, 6H),1.53-1.68 (m, 2H), 2.07 (s, 3H), 2.48-2.58 (m, 2H), 3.85 (s, 2H),4.60-4.74 (m, 1H), 6.93-7.06 (m, 4H), 7.09-7.16 (m, 1H), 7.20-7.24 (m,1H), 7.25-7.31 (m, 2H), 7.39-7.44 (m, 2H), 7.69-7.77 (m, 1H)

Example 404

3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-5-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propylpyrimidin-4(3H)-one(0.47 g) and ethanol (8 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.47 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.45 (d, J=3.8, 6H),1.52-1.66 (m, 2H), 2.08 (s, 3H), 2.51-2.56 (m, 2H), 3.05 (s, 2H), 3.84(s, 2H), 6.80 (d, J=8.5, 1H), 6.93-7.26 (m, 6H), 7.39-7.46 (m, 2H),7.69-7.73 (m, 1H)

Example 4052-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]pyrimidin-4(3H)-one

405a) [6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]boronic acid

A mixture of 5-bromo-2-chloropyridine (8.6 g), tetrahydro-2H-pyran-4-ol(5.0 g), sodium hydride (3.6 g) and dimethylformamide (80 mL) werestirred at 60° C. for 12 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The ethyl acetate layer was washed withwater and saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in dimethylformamide (100 mL),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (13.6 g),palladium acetate(II) (0.05 g) and potassium acetate (13.1 g) were addedand the mixture was stirred at 90° C. for 12 hr. The reaction mixturewas partitioned between ethyl acetate and water. The ethyl acetate layerwas washed with water and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was dissolved in tetrahydrofuran (260 mL), sodium periodate(19 g) and 0.5 M hydrochloric acid (130 mL) were added, and the mixturewas stirred at 0° C. for 2 hr, and at room temperature for 12 hr. Thesolvent was evaporated from the reaction mixture under reduced pressure,and the residue was diluted with ethyl acetate, washed with saturatedaqueous sodium hydrogen carbonate, water and saturated brine, and driedover anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (2.23 g,22%).

¹H NMR (300 MHz, CDCl₃) δ 1.74-1.89 (m, 2H), 2.02-2.15 (m, 2H),3.56-3.70 (m, 2H), 3.92-4.07 (m, 2H), 5.23-5.35 (m, 1H), 6.71 (s, 1H),6.74 (s, 1H), 6.81 (d, J=8.5, 1H), 7.72 (dd, J=8.5 2.5, 1H), 8.28 (d,J=2.5, 1H)

405b)4′-({2-methyl-6-oxo-4-propyl-1-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.5 g), [6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]boronic acid (0.49g), copper acetate (0.53 g), pyridine (0.6 mL), triethylamine (1 mL),molecular sieves 4 A (1 g) and methylene chloride (10 mL) was stirred atroom temperature for 24 hr. Ethyl acetate was added to the reactionmixture, and the insoluble solid was filtered off. The solvent of thefiltrate was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.25 g, 33%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.62-1.91 (m, 4H),2.01-2.14 (m, 2H), 2.21 (s, 3H), 2.62-2.70 (m, 2H), 3.55-3.68 (m, 2H),3.92-4.05 (m, 4H), 5.21-5.34 (m, 1H), 6.87 (d, J=8.9, 1H), 7.37-7.50 (m,7H), 7.58-7.65 (m, 1H), 7.74 (dd, J=7.7, 1.1, 1H), 8.00 (d, J=2.6, 1H)

405c)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.28 g), sodium hydrogencarbonate (0.4 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-({2-methyl-6-oxo-4-propyl-1-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.25 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL) N,N′-carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.18 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84-0.94 (m, 3H), 1.46-1.76 (m, 4H),2.00-2.13 (m, 5H), 3.27-3.37 (m, 2H), 3.44-3.56 (m, 2H), 3.81-3.96 (m,4H), 5.17-5.28 (m, 1H), 6.96 (d, J=8.7, 1H), 7.18-7.32 (m, 4H),7.46-7.58 (m, 2H), 7.63-7.72 (m, 2H), 7.79 (dd, J=8.9, 2.6, 1H), 8.19(d, J=2.3, 1H), 12.38 (s, 1H)

Example 4062-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]pyrimidin-4(3H)-one

406a)4′-({2-ethyl-6-oxo-4-propyl-1-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.52 g), [6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]boronic acid(0.49 g), copper acetate (0.53 g), pyridine (0.6 mL), triethylamine (1mL), molecular sieves 4 A (1 g) and methylene chloride (10 mL) wasstirred at room temperature for 24 hr. Ethyl acetate was added to thereaction mixture, and the insoluble solid was filtered off. The solventof the filtrate was evaporated under reduced pressure, and the residuewas purified by silica gel column chromatography to give the titlecompound as a colorless amorphous solid (0.2 g, 26%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.17 (t, J=7.5, 3H),1.65-1.91 (m, 4H), 2.06-2.13 (m, 2H), 2.31-2.48 (m, 2H), 2.65-2.73 (m,2H), 3.56-3.67 (m, 2H), 3.94-4.07 (m, 4H), 5.21-5.32 (m, 1H), 6.77-6.90(m, 1H), 7.36-7.50 (m, 7H), 7.57-7.65 (m, 1H), 7.68-7.76 (m, 1H), 7.99(d, J=2.6, 1H)

406b)2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.23 g), sodium hydrogencarbonate (0.32 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-({2-ethyl-6-oxo-4-propyl-1-[6-(tetrahydro-2H-pyran-4-yloxy)pyridin-3-yl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.2 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (4 mL) N,N′-carbonyldiimidazole (0.09 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.09 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.6 g, 27%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.4, 3H), 1.06 (t, J=7.3, 3H),1.46-1.76 (m, 4H), 1.96-2.09 (m, 2H), 2.20-2.39 (m, 2H), 2.52-2.59 (m,2H), 3.46-3.56 (m, 2H), 3.80-3.94 (m, 4H), 5.14-5.29 (m, 1H), 6.96 (d,J=8.9, 1H), 7.18-7.31 (m, 4H), 7.46-7.60 (m, 2H), 7.61-7.74 (m, 2H),7.79 (dd, J=8.8, 2.7, 1H), 8.17 (d, J=2.5, 1H), 12.38 (s, 1H)

Example 4073-[6-(2,2-dimethylpropoxy)pyridin-3-yl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

407a)4′-({1-[6-(2,2-dimethylpropoxy)pyridin-3-yl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.7 g), [6-(2,2-dimethylpropoxy)pyridin-3-yl]boronic acid (0.61 g),copper acetate (0.71 g), pyridine (0.8 mL), triethylamine (1.4 mL),molecular sieves 4 A (1.4 g) and methylene chloride (10 mL) was stirredat room temperature for 24 hr. Ethyl acetate was added to the reactionmixture, and the insoluble solid was filtered off. The solvent of thefiltrate was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.12 g, 12%).

¹H NMR (300 MHz, CDCl₃) δ 0.96-1.09 (m, 12H), 1.17 (t, J=7.4, 3H),1.65-1.80 (m, 2H), 2.29-2.51 (m, 2H), 2.64-2.72 (m, 2H), 3.92-4.06 (m,4H), 6.90 (d, J=8.7, 1H), 7.36-7.50 (m, 7H), 7.58-7.65 (m, 1H), 7.74(dd, J=7.8, 1.0, 1H), 8.00 (d, J=2.3, 1H)

407b)3-[6-(2,2-dimethylpropoxy)pyridin-3-yl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.12 g), sodium hydrogencarbonate (0.19 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-({1-[6-(2,2-dimethylpropoxy)pyridin-3-yl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (3 mL) N,N′-carbonyldiimidazole (0.06 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.08 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.4, 3H), 0.97-1.10 (m, 12H),1.51-1.65 (m, 2H), 2.19-2.42 (m, 2H), 2.52-2.58 (m, J=7.4, 2H), 3.88 (s,2H), 3.94-4.06 (m, 2H), 6.98 (d, J=8.9, 1H), 7.18-7.31 (m, 4H),7.45-7.58 (m, 2H), 7.60-7.71 (m, 2H), 7.78 (dd, J=8.8, 2.7, 1H), 8.16(d, J=2.6, 1H), 12.38 (s, 1H)

Example 4085-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propyl-3-[4-(vinyloxy)phenyl]pyrimidin-4(3H)-one

408a)3′-fluoro-4′-({2-methyl-6-oxo-4-propyl-1-[4-(vinyloxy)phenyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of3′-fluoro-4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2 g), vinyl acetate (0.82 mL), sodium carbonate (0.28 g),bis(1,5-cyclooctadiene)diiridium(I) dichloride (0.02 g) and toluene (10mL) were stirred at 100° C. for 48 hr. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(1.59 g, 75%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.60-1.75 (m, 3H), 2.18(s, 3H), 2.60-2.70 (m, 2H), 3.98 (s, 2H), 4.54 (dd, J=6.0, 1.9, 1H),4.87 (dd, J=13, 1.9, 1H), 6.65 (dd, J=13, 6.0, 1H), 7.10-7.24 (m, 6H),7.39-7.49 (m, 3H), 7.57-7.68 (m, 1H), 7.72-7.78 (m, 1H)

408b)5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-methyl-6-propyl-3-[4-(vinyloxy)phenyl]pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.72 g), sodium hydrogencarbonate (1.02 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({2-methyl-6-oxo-4-propyl-1-[4-(vinyloxy)phenyl]-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.58 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (4 mL). N,N′-carbonyldiimidazole (0.3 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.44 g, 67%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.49-1.63 (m, 2H), 2.08(s, 3H), 2.45-2.54 (m, 2H), 3.86 (s, 2H), 4.56 (dd, J=5.9, 1.6, 1H),4.79-4.85 (m, 1H), 6.90-7.04 (m, 2H), 7.11-7.23 (m, 4H), 7.34-7.42 (m,2H), 7.51-7.61 (m, 2H), 7.65-7.73 (m, 2H), 12.46 (s, 1H)

Example 4092-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-4(3H)-one

409a)4′-{[2-methyl-6-oxo-4-propyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of5-(4-bromobenzyl)-2-methyl-6-propyl-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-4(3H)-one(0.7 g), (2-cyanophenyl)boronic acid (0.36 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.07 g), 2 M aqueous sodium carbonate solution(1.5 mL) and 1,4-dioxane (15 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.61 g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.4, 3H), 1.52-1.68 (m, 4H), 2.04(s, 1H), 2.47-2.57 (m, 2H), 2.59 (s, 3H), 2.85-3.14 (m, J=8.9, 2H),3.37-3.51 (m, 2H), 3.93 (s, 2H), 4.05-4.15 (m, 2H), 4.46 (s, 1H),7.31-7.52 (m, 6H), 7.69-7.76 (m, 1H)

409b)2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(tetrahydro-2H-pyran-4-yl)pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.12 g), sodium hydrogencarbonate (0.19 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-methyl-6-oxo-4-propyl-1-(tetrahydro-2H-pyran-4-yl)-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (3 mL). N,N′-carbonyldiimidazole (0.06 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.05 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.08 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83 (t, J=7.4, 3H), 1.38-1.54 (m, 2H), 1.61(dd, J=11.5, 2.3, 2H), 2.36-2.45 (m, J=8.7, 6.8, 2H), 2.57 (s, 3H),2.71-2.90 (m, 2H), 3.33-3.45 (m, 2H), 3.81 (s, 2H), 3.93 (dd, J=11.1,4.0, 2H), 4.24-4.39 (m, 1H), 7.16-7.27 (m, 4H), 7.45-7.58 (m, 2H),7.62-7.72 (m, 2H), 12.35 (s, 1H)

Example 4102-(difluoromethyl)-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

410a)4′-{[2-(dibromomethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

Bromine (0.57 mL) was gradually added to a mixture of4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.5 g), sodium acetate (0.3 g) and acetic acid (15 mL), and the mixturewas stirred at room temperature for 12 hr. The solvent was evaporatedfrom the reaction mixture under reduced pressure, and the residue wasdiluted with ethyl acetate, washed with saturated aqueous sodiumhydrogen carbonate, water and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (1.63 g, 81%).

¹H NMR (300 MHz, CDCl₃) δ 1.03 (t, J=7.3, 3H), 1.72-1.88 (m, 2H),2.70-2.84 (m, 2H), 3.85 (s, 3H), 4.00 (s, 2H), 6.05 (s, 1H), 7.05 (d,J=8.7, 2H), 7.17-7.27 (m, 2H), 7.34-7.65 (m, 7H), 7.70-7.77 (m, 1H)

410b)4′-{[2-(difluoromethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[2-(dibromomethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), tetrabutylammonium fluoride (1.0 M, 3.3 mL) and tetrahydrofuran(10 mL) were stirred at 80° C. for 12 hr. The solvent was evaporatedfrom the reaction mixture under reduced pressure, and the residue wasdiluted with ethyl acetate, washed with water and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.16 g, 20%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.4, 3H), 1.67-1.80 (m, 2H),2.68-2.79 (m, 2H), 3.84 (s, 3H), 4.01 (s, 2H), 5.97-6.40 (m, 1H),6.97-7.07 (m, 2H), 7.15-7.23 (m, 2H), 7.36-7.50 (m, 6H), 7.57-7.65 (m,1H), 7.71-7.77 (m, 1H)

410c)2-(difluoromethyl)-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.19 g), sodium hydrogencarbonate (0.27 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-(difluoromethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.16 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.08 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.11 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.3, 3H), 1.50-1.65 (m, 2H),2.56-2.65 (m, 2H), 3.82 (s, 3H), 3.94 (s, 2H), 6.22-6.62 (m, 1H), 7.07(d, J=8.9, 2H), 7.19-7.38 (m, 6H), 7.48-7.59 (m, 2H), 7.63-7.72 (m, 2H),12.39 (s, 1H)

Example 4112-(fluoromethyl)-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

411a)4′-{[2-(fluoromethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[2-(dibromomethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), tetrabutylammonium fluoride (1.0 M, 3.3 mL) and tetrahydrofuran(10 mL) were stirred at 80° C. for 12 hr. The solvent was evaporatedfrom the reaction mixture under reduced pressure, and the residue wasdiluted with ethyl acetate, washed with water and saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.21 g, 27%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.65-1.80 (m, 2H),2.67-2.77 (m, 2H), 3.84 (s, 3H), 4.00 (s, 2H), 4.86 (s, 1H), 5.02 (s,1H), 6.99-7.08 (m, 2H), 7.15-7.21 (m, 2H), 7.36-7.51 (m, 6H), 7.58-7.65(m, 1H), 7.71-7.76 (m, 1H)

411b)2-(fluoromethyl)-3-(4-methoxyphenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.26 g), sodium hydrogencarbonate (0.37 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-{[2-(fluoromethyl)-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.21 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.11 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with saturated aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.08 g, 36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.3, 3H), 1.50-1.63 (m, 2H),2.54-2.61 (m, 2H), 3.32 (s, 3H), 3.91 (s, 2H), 4.87 (s, 1H), 5.03 (s,1H), 7.04-7.11 (m, 2H), 7.20-7.36 (m, 6H), 7.48-7.59 (m, 2H), 7.60-7.73(m, 2H), 12.39 (s, 1H)

Example 4123-{4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.87 g), 2,2-dimethyltetrahydro-2H-pyran-4-ol (0.78 g) andtriphenylphosphine (1.6 g) in tetrahydrofuran (9 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 3.2 mL). Afterstirring for 2 hr, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and a mixture of the residue, hydroxylammoniumchloride (1.4 g), sodium hydrogen carbonate (2 g) and dimethyl sulfoxide(10 mL) was stirred overnight at 90° C. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.48 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.42 g, 35%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.4), 1.19 (3H, s), 1.23 (3H,s), 1.35-1.63 (4H, m), 1.92-2.05 (2H, m), 2.06 (3H, s), 2.45-2.56 (2H,m), 3.63-3.81 (2H, m), 3.86 (2H, s), 4.69-4.82 (1H, m), 7.05-7.12 (2H,m), 7.18-7.31 (6H, m), 7.47-7.58 (2H, m), 7.62-7.72 (2H, m), 12.39 (1H,s)

Example 413

3-{4-[(2,2-dimethyltetrahydro-2H-pyran-4-yl)oxy]phenyl}-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.9 g), 2,2-dimethyltetrahydro-2H-pyran-4-ol (0.78 g) andtriphenylphosphine (1.6 g) in tetrahydrofuran (9 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 3.2 mL). Afterstirring for 2 hr, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and a mixture of the residue, hydroxylammoniumchloride (1.4 g), sodium hydrogen carbonate (2 g) and dimethyl sulfoxide(10 mL) was stirred overnight at 90° C. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.48 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.45 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.51 g, 41%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.4), 1.05 (3H, t, J=7.4),1.20 (3H, s), 1.24 (3H, s), 1.34-1.67 (4H, m), 1.92-2.07 (2H, m), 2.28(2H, q, J=7.6), 2.47-2.57 (2H, m), 3.60-3.81 (2H, m), 3.86 (2H, s),4.68-4.83 (1H, m), 7.04-7.13 (2H, m), 7.18-7.31 (6H, m), 7.47-7.58 (2H,m), 7.61-7.74 (2H, m), 12.39 (1H, s)

Example 4142-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

414a)4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-{[2-ethyl-1-(4-methoxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(26.2 g) in dichloromethane (100 mL) was added dropwise boron tribromide(1.0 M dichloromethane solution, 170 mL) at 0° C. After stirring for 18hr, ethyl acetate and water were added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated sodiumhydrogen carbonate and saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (22.1 g, 87%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 0.96-1.04 (m, 3H), 1.12 (t, J=7.4, 3H),1.64-1.79 (m, 2H), 2.38 (q, J=7.6, 2H), 2.62-2.73 (m, 2H), 4.02 (s, 2H),6.62-6.69 (m, 2H), 6.86-6.93 (m, 2H), 7.36-7.78 (m, 9H)

414b)2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) andtriphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). Afterstirring for 2 hr, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, the residue was crudely purified by silica gel columnchromatography. This was added to a mixture of hydroxylammonium chloride(0.87 g), sodium hydrogen carbonate (1.3 g) and dimethyl sulfoxide (9mL) and the mixture was stirred overnight at 90° C. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixturewas stirred at room temperature for 30 min. Tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture wasstirred overnight at 50° C. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.56 g, 35%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3), 1.04 (3H, t, J=7.3),1.21-1.67 (6H, m), 1.76-2.11 (4H, m), 2.28 (2H, q, J=7.3), 2.44-2.58(2H, m), 3.47-3.60 (1H, m), 3.86 (2H, s), 4.32-4.44 (1H, m), 4.59 (1H,d, J=4.0), 7.04 (2H, d, J=8.9), 7.16-7.32 (6H, m), 7.46-7.59 (2H, m),7.62-7.72 (2H, m), 12.38 (1H, s)

Rf=0.43 (ethyl acetate, silica gel 60 F 254 precoated TLC plates (E.Merck))

414c) Crystalline2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

(1)2-Ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(amorphous powder, 100 mg) was dissolved in ethyl acetate (1 mL) andstood overnight. The obtained colorless crystals were collected to givethe title compound (87 mg).

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):4.60, 8.38, 9.28, 9.66, 10.46, 12.26, 12.86, 13.98, 16.92, 17.32, 18.70,18.94, 19.62, 20.18, 20.98.

(2)2-Ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(amorphous powder, 100 mg) was dissolved in acetonitrile (1 mL) andstood overnight. The obtained colorless crystals were collected to givethe title compound (81 mg).

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):8.50, 11.86, 12.26, 13.98, 17.14, 18.46, 19.04, 19.28, 19.62, 20.16,20.48, 22.58, 24.60.

(3)2-Ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(amorphous powder, 100 mg) was dissolved in acetone (1 mL) and stoodovernight. The obtained colorless crystals were collected to give thetitle compound (67 mg).

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):7.36, 7.66, 11.58, 12.84, 13.28, 13.64, 14.50, 15.28, 15.50, 18.38,18.66, 19.28, 20.20, 20.70, 21.72, 22.14, 22.82.

(4)2-Ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(2.47 g) was dissolved in acetonitrile (18 ml) at 85° C. followed bybeing cooled to room temperature over 3 hr with stirring. Theprecipitate was collected, washed with acetonitrile, and dried underreduced pressure at 80° C. for 3 hr to give the title compound (1.71 g,69%) as colorless crystals.

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):8.34, 9.16, 10.64, 11.08, 11.42, 12.42, 13.18, 13.88, 14.78, 15.58,16.28, 17.10, 17.80, 18.56, 18.94, 19.18, 20.14, 20.86, 21.56, 22.04,22.44, 23.14, 23.66, 24.80, 26.18, 27.96, 29.16.

Anal calcd for C₃₆H₃N₄O₅: C, 71.27; H, 6.31; N, 9.23. Found C, 70.99; H,6.20; N, 9.14.

Example 415

2-ethyl-3-{4-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) andtriphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). Afterstirring for 2 hr, water was added and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and the residue was crudely purified by silica gelcolumn chromatography. This was added to a mixture of hydroxylammoniumchloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethylsulfoxide (9 mL) and the mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 30 min.Tetrabutylammonium fluoride (1.0 M tetrahydrofuran solution, 2.5 mL) wasadded, and the mixture was stirred overnight at 50° C. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.47 g, 29%) as an amorphoussolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3), 1.05 (3H, t, J=7.3),1.50-1.74 (8H, m), 1.76-1.93 (2H, m), 2.29 (2H, q, J=7.3), 2.46-2.58(2H, m), 3.57-3.70 (1H, m), 3.87 (2H, s), 4.42-4.54 (2H, m), 7.01-7.09(2H, m), 7.17-7.32 (6H, m), 7.47-7.59 (2H, m), 7.61-7.73 (2H, m), 12.38(1H, s)

Rf=0.46 (ethyl acetate, silica gel 60 F 254 precoated TLC plates (E.Merck))

Example 416

2-ethyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

2-Ethyl-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.4 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.42 g) were dissolved in dichloromethane (4 mL) and the mixture wasstirred for 1 hr. The reaction mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.32 g, 80%) as a colorless amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3), 1.05 (3H, t, J=7.3),1.49-1.67 (2H, m), 1.96-2.61 (12H, m), 3.87 (2H, s), 4.82-4.93 (1H, m),7.12-7.32 (8H, m), 7.46-7.59 (2H, m), 7.62-7.73 (2H, m), 12.38 (1H, s)

Example 417

3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.5 g), (2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ol (0.29 g) andtriphenylphosphine (0.58 g) in tetrahydrofuran (5 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 1.2 mL). Afterstirring for 2 hr, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, a mixture of the residue, hydroxylammonium chloride(0.77 g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10mL) was stirred overnight at 90° C. The reaction mixture was dilutedwith ethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.27 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.39 g, 57%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.4), 1.00-1.19 (9H, m),1.35-1.49 (2H, m), 1.50-1.65 (2H, m), 1.85 (2H, d, J=13.3), 2.29 (2H, q,J=7.4), 2.46-2.58 (2H, m), 3.77-3.92 (4H, m), 4.84 (1H, s), 7.06 (2H, d,J=8.7), 7.17-7.33 (6H, m), 7.46-7.59 (2H, m), 7.62-7.73 (2H, m), 12.38(1H, s)

Example 418

3-(4-{[(2R,4s,6S)-2,6-dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

3-(4-{[(2R,4s,6S)-2,6-Dimethyltetrahydro-2H-pyran-4-yl]oxy}phenyl)-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (10 mL), 8 M potassium hydroxidesolution (0.06 mL) was added, and the mixture was stirred for 1 hr. Themixture was concentrated under reduced pressure, and diisopropyl etherwas added to the residue. The precipitated solid was collected byfiltration to give the title compound (0.22 g, 69%) as an amorphoussolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.4), 1.01-1.12 (9H, m),1.34-1.49 (2H, m), 1.54-1.71 (2H, m), 1.86 (2H, d, J=12.9), 2.28 (2H, q,J=7.2), 2.52-2.62 (2H, m), 3.76-3.92 (4H, m), 4.83 (1H, s), 7.00-7.53(12H, m)

Example 4192-ethyl-3-(4-{[1-(hydroxymethyl)cyclobutyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

419a) ethyl1-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}cyclobutanecarboxylate

A solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.4 g), ethyl 1-bromocyclobutanecarboxylate (1.5 mL) and cesiumcarbonate (3 g) in dimethylacetamide (14 mL) was stirred at 100° C. for2 days. The reaction mixture was diluted with ethyl acetate, washed with5% aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound (0.76 g, 42%) as apale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.4), 1.12 (3H, t, J=7.4), 1.19(3H, t, J=7.2), 1.64-1.78 (2H, m), 1.94-2.10 (2H, m), 2.34 (2H, q,J=7.6), 2.41-2.55 (2H, m), 2.62-2.82 (4H, m), 3.96 (2H, s), 4.22 (2H, q,J=7.2), 6.75-6.82 (2H, m), 7.04-7.12 (2H, m), 7.37-7.50 (6H, m),7.57-7.66 (1H, m), 7.74 (1H, d, J=8.0)

419b)4′-{[2-ethyl-1-(4-{[1-(hydroxymethyl)cyclobutyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

Sodium borohydride (0.3 g) was dissolved in tetrahydrofuran (10 mL) andethanol (10 mL), and calcium chloride (0.44 g) was added at 0° C. Thereaction solution was stirred at 0° C. for 1 hr, ethyl1-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-ethyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}cyclobutanecarboxylate(0.76 g) was added, and the mixture was stirred overnight. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.5 g, 73%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.3), 1.15 (3H, t, J=7.3),1.60-1.94 (4H, m), 2.22-2.48 (6H, m), 2.61-2.72 (2H, m), 3.88-3.99 (4H,m), 6.91-7.15 (4H, m), 7.35-7.52 (6H, m), 7.56-7.67 (1H, m), 7.70-7.77(1H, m)

419c)2-ethyl-3-(4-{[1-(hydroxymethyl)cyclobutyl]oxy}phenyl)-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-{[1-(hydroxymethyl)cyclobutyl]oxy}phenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.5 g) and 2,6-lutidine (0.17 mL) in dichloromethane (5 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.34 mL) at 0° C.,and the mixture was stirred overnight. The reaction mixture was dilutedwith ethyl acetate, washed with 5% aqueous potassium hydrogen sulfatesolution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure. Amixture of the residue, hydroxylammonium chloride (0.67 g), sodiumhydrogen carbonate (0.97 g) and dimethyl sulfoxide (5 mL) was stirredovernight at 90° C. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (5 mL).N,N′-carbonyldiimidazole (0.23 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. Tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 1.9 mL) was added, and the mixture wasstirred overnight at 50° C. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.43 g, 76%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.4), 1.05 (3H, t, J=7.4),1.50-1.92 (4H, m), 2.12-2.76 (6H, m), 2.70-2.75 (2H, m), 3.72 (2H, d,J=5.7), 3.86 (2H, s), 6.92 (2H, d, J=9.1), 7.17-7.30 (6H, m), 7.48-7.58(2H, m), 7.62-7.73 (2H, m), 12.38 (1H, s)

Example 4206-butyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

420a) ethyl2-{4-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate

A solution of4′-{[4-butyl-1-(4-hydroxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.3 g), ethyl 2-bromo-2-methylpropanoate (2.2 mL) and cesium carbonate(4.9 g) in dimethylacetamide (23 mL) was stirred at 100° C. for 2 days.The reaction mixture was diluted with ethyl acetate, washed with 5%aqueous potassium hydrogen sulfate solution and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure and the residue was purified by silicagel column chromatography to give the title compound (2.1 g, 74%) as apale-yellow liquid.

¹H NMR (300 MHz, CDCl₃) δ 0.90-0.99 (3H, m), 1.22-1.30 (3H, m),1.34-1.50 (2H, m), 1.59 (3H, s), 1.55-1.70 (8H, m), 2.61-2.71 (2H, m),3.96 (2H, s), 4.25 (2H, q, J=7.2), 6.92-6.99 (2H, m), 7.06-7.14 (2H, m),7.36-7.53 (6H, m), 7.62 (1H, t, J=7.8), 7.74 (1H, d, J=7.6)

420b)4′-({4-butyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

Sodium borohydride (0.85 g) was dissolved in tetrahydrofuran (20 mL) andethanol (20 mL), and calcium chloride (1.2 g) was added at 0° C. Thereaction solution was stirred at 0° C. for 1 hr, ethyl2-{4-[4-butyl-5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxopyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate(2.1 g) was added, and the mixture was stirred overnight. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (1.2 g, 60%) as a pale-yellowliquid.

¹H NMR (300 MHz, CDCl₃) δ 0.94 (3H, t, J=7.3), 1.33 (6H, s), 1.35-1.51(2H, m), 1.56-1.69 (2H, m), 2.17 (3H, s), 2.61-2.71 (2H, m), 3.62 (2H,d, J=6.4), 3.97 (2H, s), 7.09-7.19 (4H, m), 7.37-7.50 (6H, m), 7.57-7.66(1H, m), 7.74 (1H, dd, J=7.7, 0.9)

420c)6-butyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of4′-({4-butyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.2 g) and 2,6-lutidine (0.34 mL) in dichloromethane (12 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.79 mL) at 0° C.,and the mixture was stirred overnight. The reaction mixture was dilutedwith ethyl acetate, washed with 5% aqueous potassium hydrogen sulfatesolution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure. Amixture of the residue, hydroxylammonium chloride (1.5 g), sodiumhydrogen carbonate (2.2 g) and dimethyl sulfoxide (10 mL) was stirredovernight at 90° C. The reaction mixture was diluted with ethyl acetate,washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.54 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL) were added, and the mixturewas stirred at room temperature for 30 min. Tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 4.4 mL) was added, and the mixture wasstirred overnight at 50° C. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.67 g, 52%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.4), 1.24 (6H, s), 1.32 (2H,dd, J=14.8, 7.6), 1.43-1.56 (2H, m), 2.06 (3H, s), 2.46-2.58 (2H, m),3.34-3.45 (2H, m), 3.86 (2H, s), 4.95 (1H, t, J=5.9), 7.10-7.31 (8H, m),7.53 (2H, dd, J=16.8, 7.8), 7.62-7.73 (2H, m), 12.39 (1H, s)

Example 421

6-butyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-onepotassium salt

6-Butyl-3-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.5 g) was dissolved in ethanol (10 mL), 8 M potassium hydroxidesolution (0.11 mL) was added, and the mixture was stirred for 1 hr. Themixture was concentrated under reduced pressure, and diisopropyl etherwas added to the residue. The precipitated solid was collected byfiltration to give the title compound (0.5 g, 94%) as an amorphoussolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.94 (3H, m), 1.24 (6H, s), 1.27-1.43(2H, m), 1.46-1.60 (2H, m), 2.04 (3H, s), 2.47-2.60 (2H, m), 3.28-3.46(2H, m), 3.81 (2H, s), 4.09 (1H, s), 7.08-7.51 (12H, m)

Example 422

2-ethyl-3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.2 g), 3-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) andtriphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). Afterstirring for 2 hr, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and a mixture of the residue, hydroxylammoniumchloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethylsulfoxide (9 mL) was stirred overnight at 90° C. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixturewas stirred at room temperature for 30 min. Tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture wasstirred overnight at 50° C. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(1.3 g, 71%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3), 1.05 (3H, t, J=7.3),1.12-1.88 (10H, m), 2.29 (2H, q, J=7.2), 2.46-2.57 (2H, m), 3.87 (2H,s), 4.27-4.78 (2H, m), 6.99-7.09 (2H, m), 7.18-7.31 (6H, m), 7.48-7.58(2H, m), 7.61-7.73 (2H, m), 12.38 (1H, s)

Example 423

2-ethyl-3-{4-[(3-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

2-Ethyl-3-{4-[(3-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.5 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.52 g) were dissolved in dichloromethane (5 mL) and the mixture wasstirred for 1 hr. The reaction mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.38 g, 76%) as a colorless amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3), 1.05 (3H, t, J=7.3),1.50-2.14 (6H, m), 2.22-2.59 (6H, m), 2.74-2.84 (1H, m), 3.86 (2H, s),4.94-5.04 (1H, m), 7.01-7.11 (2H, m), 7.17-7.32 (6H, m), 7.47-7.58 (2H,m), 7.62-7.73 (2H, m), 12.38 (1H, s)

Example 424

2-ethyl-3-{4-[(2-methyltetrahydro-2H-pyran-4-yl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.5 g), 2-methyltetrahydro-2H-pyran-4-ol (0.26 g) andtriphenylphosphine (0.58 g) in tetrahydrofuran (5 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 1.2 mL). Afterstirring for 2 hr, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and a mixture of the residue, hydroxylammoniumchloride (0.77 g), sodium hydrogen carbonate (1.1 g) and dimethylsulfoxide (10 mL) was stirred overnight at 90° C. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.37 g, 60%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.00-1.12 (6H, m),1.45-1.93 (6H, m), 2.29 (2H, q, J=7.4), 2.47-2.58 (2H, m), 3.67-3.90(5H, m), 4.80-4.87 (1H, m), 7.08 (2H, d, J=9.1), 7.17-7.32 (6H, m),7.47-7.58 (2H, m), 7.62-7.73 (2H, m), 12.38 (1H, s)

Example 425

2-ethyl-3-{4-[(3-hydroxycyclopentyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1 g), 3-{[tert-butyl(dimethyl)silyl]oxy}cyclopentanol (0.72 g) andtriphenylphosphine (0.87 g) in tetrahydrofuran (10 mL) was addeddropwise diisopropyl azodicarboxylate (1.9 M toluene solution, 1.8 mL).After stirring for 2 hr, water was added, and the mixture was extractedwith ethyl acetate. The organic layer was washed with saturated brine,and dried over anhydrous magnesium sulfate. The solvent was evaporatedunder reduced pressure, and a mixture of the residue, hydroxylammoniumchloride (1.5 g), sodium hydrogen carbonate (2.2 g) and dimethylsulfoxide (10 mL) was stirred overnight at 90° C. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.54 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.5 mL) were added, and the mixturewas stirred at room temperature for 30 min. Tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 4.4 mL) was added, and the mixture wasstirred overnight at 50° C. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.98 g, 74%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.4), 1.05 (3H, t, J=7.4),1.20-1.32 (2H, m), 1.50-2.06 (3H, m), 2.23-2.44 (4H, m), 2.44-2.58 (4H,m), 3.86 (2H, s), 4.66 (1H, d, J=4.2), 4.76 (1H, s), 6.99 (2H, d,J=9.1), 7.18-7.32 (6H, m), 7.47-7.58 (2H, m), 7.62-7.73 (2H, m), 12.38(1H, s)

Example 426

2-ethyl-3-{4-[(3-oxocyclopentyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

2-Ethyl-3-{4-[(3-hydroxycyclopentyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.5 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.54 g) were dissolved in dichloromethane (10 mL) and the mixture wasstirred for 1 hr. The reaction mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.32 g, 64%) as a colorless amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.4),1.50-1.66 (2H, m), 2.12-2.42 (7H, m), 2.46-2.59 (2H, m), 2.74 (1H, dd,J=18.2, 5.7), 3.87 (2H, s), 5.19 (1H, s), 7.03-7.12 (2H, m), 7.17-7.34(6H, m), 7.47-7.58 (2H, m), 7.61-7.73 (2H, m), 12.38 (1H, s)

Example 427

6-butyl-3-[4-(2-methoxy-1,1-dimethylethoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A solution of4′-({4-butyl-1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.52 g), 60% sodium hydride (0.08 g) and iodomethane (0.28 g) in DMF (5mL) solution was stirred at room temperature for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with 5% aqueous potassiumhydrogen sulfate solution and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. A mixture of the residue, hydroxylammonium chloride (0.69 g),sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (5 mL) wasstirred overnight at 90° C. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (5 mL).N,N′-carbonyldiimidazole (0.24 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.14 g, 24%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.25-1.40 (8H, m),1.41-1.57 (2H, m), 2.06 (3H, s), 2.47-2.57 (2H, m), 3.33 (3H, s), 3.36(2H, s), 3.86 (2H, s), 7.06-7.14 (2H, m), 7.18-7.31 (6H, m), 7.52 (2H,dd, J=16.7, 7.6), 7.61-7.72 (2H, m), 12.39 (1H, s)

Example 428

6-butyl-2-methyl-3-{4-[(2-methyltetrahydro-2H-pyran-4-yl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.5 g), 2-methyltetrahydro-2H-pyran-4-ol (0.26 g) andtriphenylphosphine (0.58 g) in tetrahydrofuran (5 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 1.2 mL). Afterstirring for 2 hr, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and a mixture of the residue, hydroxylammoniumchloride (0.77 g), sodium hydrogen carbonate (1.1 g) and dimethylsulfoxide (10 mL) was stirred overnight at 90° C. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.36 g, 53%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.4), 1.08 (3H, d, J=6.4),1.24-1.60 (5H, m), 1.69-1.94 (3H, m), 2.07 (3H, s), 2.47-2.57 (2H, m),3.67-3.90 (5H, m), 4.84 (1H, s), 7.08 (2H, d, J=8.7), 7.19-7.31 (6H, m),7.46-7.59 (2H, m), 7.61-7.73 (2H, m), 12.39 (1H, s)

Example 429

2-ethyl-3-{4-[(1-methylpiperidin-4-yl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.5 g), 1-methylpiperidin-4-ol (0.26 g) and triphenylphosphine (0.58 g)in tetrahydrofuran (5 mL) was added dropwise diisopropylazodicarboxylate (1.9 M toluene solution, 1.2 mL). After stirring for 2hr, water was added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, and a mixture of the residue, hydroxylammonium chloride (0.77g), sodium hydrogen carbonate (1.1 g) and dimethyl sulfoxide (10 mL) wasstirred overnight at 90° C. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. The residue was dissolved in tetrahydrofuran (10 mL).N,N′-carbonyldiimidazole (0.27 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.16 g, 25%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.4), 1.01-1.08 (3H, m),1.50-1.84 (4H, m), 1.96-2.09 (2H, m), 2.28 (2H, q, J=7.2), 2.42 (3H, s),2.48-2.65 (4H, m), 2.84-2.97 (2H, m), 3.85 (2H, s), 4.48-4.59 (1H, m),7.09 (2H, d, J=9.1), 7.18-7.30 (6H, m), 7.42-7.53 (2H, m), 7.57-7.65(2H, m)

Example 430

6-butyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) andtriphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). Afterstirring for 2 hr, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and a mixture of the residue, hydroxylammoniumchloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethylsulfoxide (9 mL) was stirred overnight at 90° C. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixturewas stirred at room temperature for 30 min. Tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture wasstirred overnight at 50° C. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.45 g, 33%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.82-0.90 (3H, m), 1.20-1.73 (10H, m),1.78-1.93 (2H, m), 2.07 (3H, s), 2.46-2.57 (2H, m), 3.57-3.69 (1H, m),3.86 (2H, s), 4.43-4.56 (2H, m), 7.05 (2H, d, J=9.1), 7.17-7.33 (6H, m),7.46-7.58 (2H, m), 7.62-7.74 (2H, m), 12.39 (1H, s)

Example 431

6-butyl-3-{4-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of6-butyl-3-(4-hydroxyphenyl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(1.2 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanol (1.2 g) andtriphenylphosphine (1.4 g) in tetrahydrofuran (12 mL) was added dropwisediisopropyl azodicarboxylate (1.9 M toluene solution, 2.8 mL). Afterstirring for 2 hr, water was added, and the mixture was extracted withethyl acetate. The organic layer was washed with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure, and a mixture of the residue, hydroxylammoniumchloride (0.87 g), sodium hydrogen carbonate (1.3 g) and dimethylsulfoxide (9 mL) was stirred overnight at 90° C. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (9 mL). N,N′-carbonyldiimidazole (0.3 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, and the mixturewas stirred at room temperature for 30 min. Tetrabutylammonium fluoride(1.0 M tetrahydrofuran solution, 2.5 mL) was added, and the mixture wasstirred overnight at 50° C. The reaction mixture was diluted with ethylacetate, washed with 5% aqueous potassium hydrogen sulfate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.37 g, 28%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.89 (3H, m), 1.22-1.56 (8H, m),1.78-1.89 (2H, m), 1.98-2.09 (5H, m), 2.47-2.56 (2H, m), 3.47-3.61 (1H,m), 3.86 (2H, s), 4.31-4.45 (1H, m), 4.59 (1H, d, J=4.2), 7.05 (2H, d,J=9.1), 7.18-7.31 (6H, m), 7.47-7.58 (2H, m), 7.62-7.73 (2H, m), 12.39(1H, s)

Example 432

6-butyl-2-methyl-3-{4-[(4-oxocyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

6-Butyl-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.4 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.42 g) were dissolved in dichloromethane (4 mL) and the mixture wasstirred for 1 hr. The reaction mixture was diluted with ethyl acetate,washed with saturated aqueous sodium hydrogen carbonate solution andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compound(0.37 g, 93%) as a colorless amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.90 (3H, m), 1.21-1.57 (4H, m),1.96-2.24 (7H, m), 2.30-2.56 (6H, m), 3.86 (2H, s), 4.82-4.93 (1H, m),7.11-7.35 (8H, m), 7.47-7.59 (2H, m), 7.62-7.74 (2H, m), 12.39 (1H, s)

Example 4332-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

433a) 4-hydroxycyclohexyl benzoate

A mixture of benzoyl chloride (50 mL), cyclohexanediol (150 g), pyridine(105 mL) and tetrahydrofuran (1300 mL) was stirred at room temperatureovernight. The reaction mixture was concentrated under reduced pressure,the residue was diluted with ethyl acetate, successively washed withsaturated aqueous sodium hydrogen carbonate, water, and brine, driedover anhydrous magnesium sulfate, and concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound as a colorless oil (81.5 g, 86%).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.42-2.19 (m, 9H), 3.75-3.91 (m,1H), 4.96-5.20 (m, 1H), 7.38-7.60 (m, 3H), 8.01-8.10 (m, 2H)

433b) cis-4-hydroxycyclohexyl benzoate

To a solution of 4-hydroxycyclohexyl benzoate (81.5 g) and Lipase QLG(40 g) in diisopropyl ether (800 mL) was added vinyl acetate (120 mL) atroom temperature. After being stirred at room temperature for 2 hr,Lipase QLG was filtered off. The filtrate was concentrated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound as a colorless solid (37.5 g, 46%).

¹H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.63-1.89 (m, 7H), 1.94-2.13 (m,2H), 3.77-3.90 (m, 1H), 5.07-5.21 (m, 1H), 7.37-7.61 (m, 3H), 8.00-8.11(m, 2H)

433c)2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

2-Ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.1 g) was dissolved in ethanol (1 mL), 8 M potassium hydroxidesolution (0.021 mL) was added, and the mixture was stirred for 1 hr. Themixture was concentrated under reduced pressure, and diisopropyl etherwas added to the residue. The precipitated solid was collected byfiltration to give the title compound (0.05 g, 47%) as an amorphoussolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.3), 1.04 (3H, t, J=7.3),1.21-1.52 (4H, m), 1.54-1.70 (2H, m), 1.78-1.89 (2H, m), 1.98-2.08 (2H,m), 2.27 (2H, q, J=7.3), 2.56 (2H, dd, J=8.4, 6.7), 3.47-3.60 (1H, m),3.81 (2H, s), 4.31-4.45 (1H, m), 4.59 (1H, d, J=4.1), 6.99-7.07 (2H, m),7.11-7.50 (10H, m)

433d) Crystalline2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

(1a) To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(45.0 g), cis-4-hydroxycyclohexyl benzoate (44.1 g) andtriphenylphosphine (52.5 g) in tetrahydrofuran (600 mL) was addeddropwise diisopropyl azodicarboxylate (1.9 M toluene solution, 105 mL)over a period of 30 min. After stirring for 20 min, water was addedthereto, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure,hexane and ethyl acetate was added to the residue. The obtained whitesolid was removed by filtration. The filtrate was evaporated underreduced pressure. The residue was crudely purified by silica gel columnchromatography. This was added to a mixture of hydroxylammonium chloride(102.8 g), sodium hydrogen carbonate (149.2 g) and dimethyl sulfoxide(680 mL) and the resulting mixture was stirred overnight at 90° C. Thereaction mixture was diluted with ethyl acetate, washed with water andsaturated brine successively, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure. To a mixtureof the residue in tetrahydrofuran (800 mL) were addedN,N′-carbonyldiimidazole (48.6 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene(44.8 mL) in turn, and the mixture was stirred at room temperature for30 min. The reaction mixture was diluted with ethyl acetate, washed with1M hydrochloric acid and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure. To a mixture of the residue in methanol (1500 mL) was addedsodium methoxide (28 wt % in methanol, 85.3 g) at room temperature, andthe mixture was stirred at this temperature overnight. The mixture wasevaporated under reduced pressure, the residue was dissolved intetrahydrofuran (1500 mL). To the resulting tetrahydrofuran solutionwere added N,N′-carbonyldiimidazole (18.0 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (16.6 mL) in turn, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with 1M hydrochloric acid and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure to give a crude solid. Thecrude solid was recrystallized from hexane/ethyl acetate (1:1) to givecolorless crystals. The crystals were dissolved in acetone (1000 mL). Tothe acetone solution was added 8M potassium hydroxide solution (27.6mL), and the mixture was stirred overnight to give a colorless solid(130 g, 91%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.4) 1.04 (3H, t, J=7.4)1.27-1.48 (4H, m) 1.57-1.70 (2H, m) 1.77-1.92 (2H, m) 1.98-2.07 (2H, m)2.27 (2H, d, J=7.4) 2.52-2.60 (2H, m) 3.44-3.61 (1H, m) 3.81 (2H, s)4.29-4.45 (1H, m) 4.64 (1H, s) 7.03 (2H, d, J=8.9) 7.11-7.51 (10H, m)

(1b) A solution of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt (226.9 g) in ethanol (900 mL) was stirred at 60° C. for 2hr. The mixture was allowed to cool to room temperature, an insolublematerial was filtered off. The filtrate was stirred at 60° C., andheptane (600 mL) was added thereto over a period of 1 hr. The mixturewas allowed to cool to room temperature, and heptane (600 mL) was addedthereto. The resulting solution was stirred at this temperatureovernight. The obtained colorless crystals were collected, washed withheptane/ethanol (2:1) and dried under reduced pressure at 50° C. for 6hr to give the title compound (191.2 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.3), 1.04 (3H, t, J=7.3),1.21-1.52 (4H, m), 1.54-1.70 (2H, m), 1.78-1.89 (2H, m), 1.98-2.08 (2H,m), 2.27 (2H, q, J=7.3), 2.56 (2H, dd, J=8.4, 6.7), 3.47-3.60 (1H, m),3.81 (2H, s), 4.31-4.45 (1H, m), 4.59 (1H, d, J=4.1), 6.99-7.07 (2H, m),7.11-7.50 (10H, m)

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):4.32, 8.70, 9.86, 12.76, 13.10, 15.48, 18.36, 19.68, 20.62, 21.36,21.76, 22.04, 22.44, 23.10, 24.22, 24.62, 27.94, 28.24.

(2) A mixture of2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt (5.0 g) and isopropyl alcohol (50 mL) was stirred at 90°C. for 30 min. The mixture was cooled to room temperature and aninsoluble material was filtered off. To the filtrate was added1-methylethyl acetate (60 mL) dropwise, and the obtained colorlesscrystals were collected. The crystals were washed with isopropyl alcoholto give the title compound (4.5 g).

Anal. Calcd for C₃₆H₃₇N₄O₅K: C, 67.06; H, 5.78; N, 8.69%. Found: C,64.69; H, 5.91; N, 8.47%

Powder X-ray diffraction (Cu—Kα radiation, diffraction angle: 2θ(°)):6.32, 6.84, 8.90, 14.36, 16.64, 17.96, 19.18, 19.94, 21.82, 22.04,22.90, 23.62, 24.92.

Example 434

2-ethyl-3-{4-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt

2-Ethyl-3-{4-[(cis-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (10 mL), 8 M potassium hydroxidesolution (0.63 mL) was added, and the mixture was stirred for 1 hr. Themixture was concentrated under reduced pressure, and acetone and hexanewere added to the residue. The precipitated solid was collected byfiltration to give the title compound (0.32 g, 100%) as an amorphoussolid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.3), 1.04 (3H, t, J=7.3),1.52-1.72 (8H, m), 1.77-1.93 (2H, m), 2.28 (2H, q, J=7.3), 2.56 (2H, dd,J=8.3, 6.8), 3.55-3.70 (1H, m), 3.82 (2H, s), 4.42-4.52 (2H, m),7.00-7.08 (2H, m), 7.11-7.49 (10H, m)

Example 435

-   2-ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one    sodium salt

2-Ethyl-3-{4-[(trans-4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (10 mL), 8 M sodium hydroxide solution(0.63 mL) was added, and the mixture was stirred for 1 hr. The mixturewas concentrated under reduced pressure, and acetone and hexane wereadded to the residue. The precipitated solid was collected by filtrationto give the title compound (0.3 g, 96%) as an amorphous solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.3), 1.04 (3H, t, J=7.3),1.21-1.52 (4H, m), 1.54-1.70 (2H, m), 1.78-1.89 (2H, m), 1.98-2.08 (2H,m), 2.27 (2H, q, J=7.3), 2.56 (2H, dd, J=8.4, 6.7), 3.47-3.60 (1H, m),3.81 (2H, s), 4.31-4.45 (1H, m), 4.59 (1H, d, J=4.1), 6.99-7.07 (2H, m),7.11-7.50 (10H, m)

Example 436

3-{4-[(4-hydroxycycloheptyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.11 g), 4-{[tert-butyl(dimethyl)silyl]oxy}cycloheptanol (0.29 g) andtriphenylphosphine (0.18 g) in tetrahydrofuran (2 mL) was addeddiisopropyl azodicarboxylate (1.9 M toluene solution, 0.36 mL), and themixture was stirred for 1 hr. Ethyl acetate and water were added to thereaction mixture, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with saturated brine and dried over anhydrousmagnesium sulfate. The solvent was evaporated and the residue wascrudely purified by silica gel column chromatography. This was added toa mixture of hydroxylammonium chloride (0.47 g), sodium hydrogencarbonate (0.76 g) and dimethyl sulfoxide (3 mL), which had been stirredat 40° C. for 30 min, and the mixture was stirred at 90° C. for 18 hr.The reaction mixture was allowed to cool to room temperature, ethylacetate and water were added, and the mixture was extracted with ethylacetate. The organic layer was washed with saturated brine and driedover anhydrous magnesium sulfate. The solvent was evaporated and theresidue was dissolved in tetrahydrofuran (3 mL).N,N′-carbonyldiimidazole (0.088 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.081 mL) were added, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (2 mL), tetrabutylammonium fluoride (1.0 Mtetrahydrofuran solution, 0.9 mL) was added, and the mixture was stirredat 70° C. for 5 hr. The reaction mixture was allowed to cool to roomtemperature, ethyl acetate and water were added, and the mixture wasextracted with ethyl acetate. The organic layer was washed withsaturated brine and dried over anhydrous magnesium sulfate. The solventwas evaporated and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.15 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.21-2.09 (m, 15H),2.47-2.54 (m, 2H), 3.64-3.76 (m, 1H), 3.86 (s, 2H), 4.41-4.61 (m, 2H),6.95-7.73 (m, 12H), 12.33 (s, 1H)

Example 437

2-methyl-3-{4-[(4-oxocycloheptyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-{4-[(4-hydroxycycloheptyl)oxy]phenyl}-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.10 g) in methylene chloride (2 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.11 g),and the mixture was stirred for 1 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.051 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.46-2.12 (m, 11H),2.41-2.57 (m, 6H), 3.86 (s, 2H), 4.60-4.71 (m, 1H), 7.04-7.72 (m, 12H),12.38 (s, 1H)

Example 4383-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

438a)4′-({1-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of methyl2-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate(1.15 g) in tetrahydrofuran (10 mL) was added methylmagnesium bromide(1.0 M diethyl ether solution, 2.15 mL) at −78° C., and the mixture wasstirred for 6 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.75 g, 65%).

¹H NMR (300 MHz, CHLOROFORM-d) δ 1.01 (t, J=7.2, 3H), 1.30 (s, 6H), 1.34(s, 6H), 1.64-1.76 (m, 2H), 2.18 (s, 3H), 2.62-2.70 (m, 3H), 3.97 (s,2H), 7.09-7.77 (m, 12H)

438b)3-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogencarbonate (2.62 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.96 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.41g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.78 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.25 (s, 6H), 1.26 (s,6H), 1.47-1.62 (m, 2H), 2.06 (s, 3H), 2.48-2.55 (m, 2H), 3.87 (s, 2H),4.45 (s, 1H), 7.09-7.74 (m, 12H), 12.38 (s, 1H)

Example 4393-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

439a)4′-({1-[4-(1,1-dimethyl-2-oxoethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({1-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.01 g) in methylene chloride (10 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (1.26 g),and the mixture was stirred for 1 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.79 g, 79%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3, 3H), 1.48 (s, 6H), 1.59-1.78(m, 2H), 2.16 (s, 3H), 2.61-2.71 (m, 2H), 3.96 (s, 2H), 6.93-7.78 (m,12H), 9.83 (s, 1H)

439b)4′-({1-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-({1-[4-(1,1-dimethyl-2-oxoethoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.15 g) in tetrahydrofuran (10 mL) was added methylmagnesium bromide(3.0 M diethyl ether solution, 0.78 mL) at −78° C., and the mixture wasstirred for 3 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.60 g, 74%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.20-1.30 (m, 9H),1.61-1.78 (m, 2H), 2.17 (s, 3H), 2.59 (d, J=3.8, 1H), 2.61-2.69 (m, 2H),3.82-3.93 (m, 1H), 3.97 (s, 2H), 7.09-7.77 (m, 12H)

439c)3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.70 g), sodium hydrogencarbonate (2.62 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.60 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (6 mL). N,N′-carbonyldiimidazole (0.22g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a pale-yellow amorphous solid (0.46 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.16 (d, J=6.4, 3H),1.19 (s, 6H), 1.25 (s, 6H), 1.47-1.62 (m, 2H), 2.06 (s, 3H), 2.48-2.55(m, 2H), 3.62-3.74 (m, 1H), 3.87 (s, 2H), 4.78 (d, J=5.3, 1H), 7.06-7.73(m, 12H), 12.38 (s, 1H)

Example 440

3-[4-(1,1-dimethyl-2-oxopropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.26 g) in methylene chloride (3 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.28 g),and the mixture was stirred for 1 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.19 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.48 (s, 6H), 1.49-1.62(m, 2H), 2.05 (s, 3H), 2.27 (s, 3H), 2.47-2.55 (m, 2H), 3.86 (s, 2H),6.85-7.75 (m, 12H), 12.38 (s, 1H)

Example 4415-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-6-propylpyrimidin-4(3H)-one

441a) ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate

To a suspension of sodium hydride (60% in oil, 0.89 g) intetrahydrofuran (70 ml) was added a solution of ethyl 3-oxohexanoate(5.45 g) in tetrahydrofuran (20 ml) dropwise at room temperature. Afterbeing stirred at room temperature for 1 hr,4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (5.0 g) was added tothe mixture and the mixture was stirred at room temperature for 15 hr.Ethyl acetate and saturated aqueous ammonium chloride solution wereadded to the mixture. The layers were separated and the aqueous layerwas extracted with ethyl acetate. The combined organic layer wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound as a pale yellow oil (5.18 g, 82%).

¹H NMR (300 MHz, CDCl₃) δ 0.87 (t, J=7.4 Hz, 3H), 1.22 (t, J=7.2 Hz,3H), 1.51-1.67 (m, 2H), 2.36-2.68 (m, 2H), 3.14-3.33 (m, 2H), 3.91 (t,J=7.6 Hz, 1H), 4.16 (qd, J=7.1, 0.7 Hz, 2H), 7.18-7.80 (m, 7H)

441b)3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a suspension of acetamidine hydrochloride (2.67 g) in methanol (50ml) was added sodium methoxide (28% in methanol, 8.2 mL) dropwise,followed by addition of a solution of ethyl2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (5.18 g) inmethanol (20 ml) at room temperature. After being stirred at roomtemperature for 15 hr, ethyl acetate and saturated aqueous ammoniumchloride solution were added. The layers were separated and the aqueouslayer was extracted with ethyl acetate. The combined organic layer wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The resultingsolid was collected and washed with diisopropyl ether to give the titlecompound as a white solid (3.97 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (t, J=7.4 Hz, 3H), 1.44-1.59 (m, J=7.5,7.5, 7.5, 7.5, 7.3 Hz, 2H), 2.26 (s, 3H), 2.40-2.49 (m, 2H), 3.84 (s,2H), 7.00-8.18 (m, 7H), 12.35 (s, 1H)

441c)3′-fluoro-4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.0 g), (4-methoxyphenyl)boronic acid (2.0 g), triethylamine (4.0 mL),pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride(30 mL) was added copper(II) acetate (1.0 g), and the mixture wasstirred at room temperature for 4 days. The reaction mixture was dilutedwith ethyl acetate, the insoluble material was filtered off throughcelite, and the filtrate was concentrated. The residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (2.35 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.3 Hz, 3H), 1.63-1.76 (m, 2H),2.18 (s, 3H), 2.60-2.69 (m, 2H), 3.85 (s, 3H), 3.98 (s, 2H), 6.97-7.79(m, 11H)

441d)3′-fluoro-4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a solution of3′-fluoro-4′-{[1-(4-methoxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(2.35 g) in methylene chloride (10 mL) was added tribromoborane (1.0 Mmethylene chloride solution, 20 mL) at room temperature. After beingstirred at room temperature for 12 hr, ethyl acetate and water wereadded, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as a whitesolid (2.25 g, 99%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.3 Hz, 3H), 1.57-1.76 (m, 3H),2.18 (s, 3H), 2.61-2.70 (m, 2H), 4.03 (s, 2H), 6.62-7.79 (m, 11H)

441e) methyl2-{4-[5-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate

To a solution of3′-fluoro-4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g) and methyl 2-bromo-2-methylpropanoate (1.0 g) inN,N-dimethylformamide (10 mL) was added cesium carbonate (0.72 g), andthe mixture was stirred at 80° C. for 12 hr. After allowing to cool toroom temperature, ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.58 g, 96%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.3 Hz, 3H), 1.60-1.78 (m, 8H),2.16 (s, 3H), 2.59-2.68 (m, 2H), 3.78 (s, 3H), 3.98 (s, 2H), 6.89-7.78(m, 11H)

441f)3′-fluoro-4′-({1-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of methyl2-{4-[5-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate(1.00 g) in tetrahydrofuran (8 mL) was added methylmagnesium bromide(3.0 M diethyl ether solution, 1.84 mL) at −78° C., and the mixture wasstirred for 3 hr. Ethyl acetate and water were added to the reactionmixture, and the mixture was extracted with ethyl acetate. The organiclayer was washed with saturated brine and dried over anhydrous magnesiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as apale-yellow amorphous solid (0.77 g, 77%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.30 (s, 6H), 1.34 (s,6H), 1.63-1.75 (m, 2H), 2.18 (s, 3H), 2.60-2.68 (m, 3H), 3.99 (s, 2H),7.09-7.78 (m, 11H)

441 g)5-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.97 g), sodium hydrogencarbonate (1.40 g) and dimethyl sulfoxide (7 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-({1-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.77 g) was added, and the mixture was stirred at 90° C. for 18 hr. Thereaction mixture was allowed to cool to room temperature, ethyl acetateand water were added, and the mixture was extracted with ethyl acetate.The organic layer was washed with saturated brine and dried overanhydrous magnesium sulfate. The solvent was evaporated and the residuewas dissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 3 hr. The reactionmixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.71 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3, 3H), 1.24 (s, 6H), 1.25 (s,6H), 1.50-1.63 (m, 2H), 2.07 (s, 3H), 2.46-2.54 (m, 2H), 3.86 (s, 2H),4.44 (s, 1H), 6.98-7.74 (m, 11H), 12.46 (s, 1H)

Example 4422-ethyl-3-{[(2RS,4s,6SR)-4-hydroxy-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

442a) (3s,5RS,7SR)-5,7-dimethyl-1,6-dioxaspiro[2.5]octane

To a solution of trimethylsulfoxonium iodide (6.2 g) in dimethylsulfoxide (50 mL) was added sodium hydride (1.1 g, 60%) and the mixturewas stirred for 30 min. To the reaction mixture was added a solution of(2R,6S)-2,6-dimethyltetrahydro-4H-pyran-4-one (3 g) in dimethylsulfoxide (10 mL), and the mixture was stirred at room temperature for30 min. The reaction mixture was poured into ice water, and the mixturewas extracted with ethyl acetate, washed with saturated brine, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give the title compound as a colorless oil (2.5 g, 74%).

¹H NMR (300 MHz, CDCl₃) δ 1.10-1.32 (8H, m), 1.71-1.87 (2H, m), 2.67(2H, s), 3.73-3.90 (2H, m)

442b)4′-[(2-ethyl-1-{[(2RS,4s,6SR)-4-hydroxy-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g) in N,N-dimethylacetamide (20 mL) were added(3s,5RS,7SR)-5,7-dimethyl-1,6-dioxaspiro[2.5]octane (0.6 g) and cesiumcarbonate (1.4 g), and the mixture was stirred at 120° C. for 24 hr. Themixture was allowed to cool to room temperature. The insoluble materialwas filtered off, diluted with ethyl acetate, washed with 1 Mhydrochloric acid, saturated sodium hydrogen carbonate and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel chromatography to give the title compound as a pale-yellow solid(0.38 g, 27%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (3H, t, J=7.2), 1.18 (6H, d, J=6.3),1.20-1.39 (5H, m), 1.47-1.78 (4H, m), 2.55-2.66 (2H, m), 2.79 (2H, q,J=7.2), 3.82-3.97 (2H, m), 3.97 (2H, s), 4.14 (2H, s), 4.99 (1H, s),7.29-7.51 (6H, m), 7.57-7.66 (1H, m), 7.74 (1H, d, J=7.8)

442c)2-ethyl-3-{[(2RS,4s,6SR)-4-hydroxy-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.9 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-[(2-ethyl-1-{[(2RS,4s,6SR)-4-hydroxy-2,6-dimethyltetrahydro-2H-pyran-4-yl]methyl}-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.38 g) was added, and the mixture was stirred at 90° C. for 8 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.12 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.2 g, 47%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 0.94-1.08 (6H, m),1.09-1.29 (5H, m), 1.33-1.46 (2H, m), 1.46-1.63 (2H, m), 2.41-2.50 (2H,m), 2.98 (2H, q, J=7.2), 3.56-3.74 (2H, m), 3.86 (2H, s), 4.04 (2H, s),4.92 (1H, s), 7.13-7.29 (4H, m), 7.42-7.58 (2H, m), 7.59-7.72 (2H, m),12.38 (1H, br)

Example 4432-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[4-(4-oxopiperidin-1-yl)phenyl]-6-propylpyrimidin-4(3H)-one

443a)4′-{[1-(4-bromophenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a suspension of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2 g), 4-bromophenylboronic acid (2.3 g), triethylamine (3.9 mL),pyridine (2.3 mL) and molecular sieves 4 A (4 g) in dichloromethane (20mL) was added copper(II) acetate (2.0 g) and the mixture was stirred for2 days. The reaction mixture was diluted with ethyl acetate, theinsoluble material was filtered off through celite, and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.6 g,56%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.2), 1.15 (3H, t, J=7.2),1.63-1.80 (2H, m), 2.35 (2H, q, J=7.2), 2.62-2.72 (2H, m), 3.96 (2H, s),7.12 (2H, d, J=8.4), 7.36-7.51 (6H, m), 7.57-7.69 (3H, m), 7.74 (1H, d,J=8.1)

443b)4′-({1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a solution of4′-{[1-(4-bromophenyl)-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.6 g), 1,1′-binaphthalene-2,2′-diylbis(diphenylphosphine) (0.29 g),1,4-dioxa-8-azaspiro[4.5]decane (0.9 g) and sodium tert-butoxide (0.45g) in toluene (40 mL) was added tris(dibenzylideneacetone)dipalladium(0.14 g), and the mixture was stirred at 100° C. for 12 hr under anargon atmosphere. The reaction mixture was diluted with ethyl acetate,and the insoluble material was filtered off through celite. The filtratewas washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound as a colorless solid (1.1 g, 60%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.2), 1.14 (3H, t, J=7.2),1.63-1.77 (2H, m), 1.79-1.88 (4H, m), 2.39 (2H, q, J=7.2), 2.61-2.71(2H, m), 3.34-3.43 (4H, m), 3.96 (2H, s), 4.00 (4H, s), 6.96-7.10 (4H,m), 7.36-7.51 (6H, m), 7.56-7.66 (1H, m), 7.73 (1H, d, J=7.8)

443c)3-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (2.6 g), sodium hydrogencarbonate (3.2 g) and dimethyl sulfoxide (20 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(1.1 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (20 mL). N,N′-carbonyldiimidazole (0.46 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.45 g, 38%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (3H, t, J=7.2), 1.13 (3H, t, J=7.2),1.71-1.87 (6H, m), 2.37 (2H, q, J=7.2), 2.66-2.75 (2H, m), 3.33-3.43(4H, m), 3.90 (2H, s), 4.00 (4H, s), 6.92-7.02 (4H, m), 7.20 (2H, d,J=8.4), 7.31 (2H, d, J=8.4), 7.38-7.49 (2H, m), 7.54-7.62 (1H, m), 7.79(1H, d, J=7.2)

443d)2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-3-[4-(4-oxopiperidin-1-yl)phenyl]-6-propylpyrimidin-4(3H)-one

A solution of3-[4-(1,4-dioxa-8-azaspiro[4.5]dec-8-yl)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.45 g) in tetrahydrofuran (10 mL)-1 M hydrochloric acid (10 mL) wasstirred at 60° C. for 2 days. The reaction mixture was diluted withethyl acetate, washed with saturated aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (0.45 g, 38%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.49-1.65 (2H, m), 2.31 (2H, q, J=7.2), 2.42-2.58 (6H, m), 3.67 (4H, t,J=6.0), 3.87 (2H, s), 7.07-7.31 (8H, m), 7.47-7.59 (2H, m), 7.62-7.73(2H, m), 12.38 (1H, br)

Example 4442-ethyl-3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

444a) 3-(4-bromophenoxy)-3-methylbutan-2-ol

To a solution of 2-(4-bromophenoxy)-2-methylpropanal (5.3 g) intetrahydrofuran (100 mL) was added methylmagnesium bromide (9.5 mL, 3 Mdiethyl ether solution) at −20° C., and the mixture was stirred for 1hr. A saturated ammonium chloride solution was added to the reactionmixture, and the mixture was extracted with ethyl acetate, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonatesolution and saturated brine, and dried over anhydrous sodium sulfate.The solvent was evaporated under reduced pressure. The residue waspurified by silica gel column chromatography to give the title compoundas a colorless solid (4.0 g, 70%).

¹H NMR (300 MHz, CDCl₃) δ 1.15-1.25 (9H, m), 2.59 (1H, d, J=3.3),3.77-3.90 (1H, m), 6.86 (2H, d, J=8.7), 7.79 (2H, d, J=8.7)

444b)tert-butyl{1,2-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propoxy}dimethylsilane

To a solution of 3-(4-bromophenoxy)-3-methylbutan-2-ol (4.0 g) and2,6-lutidine (4.6 mL) in dichloromethane (40 mL) was addedtert-butyl(dimethyl)silyl trifluoromethanesulfonate (4.2 mL) underice-cooling, and the mixture was stirred for 1 hr. The reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid andthen with saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin N,N-dimethylformamide (50 mL),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (4.7 g),potassium acetate (4.5 g) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.37 g) wereadded, and the mixture was stirred at 90° C. for 12 hr under an argonatmosphere. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off through celite. The filtrate waswashed with 1 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound as a pale-yellow oil (5.8 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 0.06 (3H, s), 0.09 (3H, s), 0.90 (9H, s),1.15-1.37 (21H, m), 3.81-3.91 (1H, m), 6.97 (2H, d, J=8.4), 7.71 (2H, d,J=8.4)

444c)[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylpropoxy)phenyl]boronicacid

tert-Butyl{1,2-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]propoxy}dimethylsilane(5.8 g) was dissolved in 1 M hydrochloric acid (20 mL)-tetrahydrofuran(20 mL)-water (20 mL), sodium periodate (5.9 g) was added, and themixture was stirred at room temperature for 3 hr. The reaction mixturewas diluted with water, extracted with ethyl acetate, washed with 1 Mhydrochloric acid, saturated aqueous sodium hydrogen carbonate solutionand saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure and the title compound asa pale-yellow solid (1.1 g, 23%).

¹H NMR (300 MHz, CDCl₃) δ 0.09 (3H, s), 0.17 (3H, s), 0.92 (9H, s),1.17-1.31 (9H, m), 3.82-3.97 (1H, m), 7.09 (2H, d, J=8.4), 8.12 (2H, d,J=8.4)

444d)4′-({1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylpropoxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

To a suspension of4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(0.56 g),[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylpropoxy)phenyl]boronicacid (1.1 g), triethylamine (1.1 mL), pyridine (0.63 mL) and molecularsieves 4 A (1.1 g) in dichloromethane (10 mL) was added copper(II)acetate (0.56 g) and the mixture was stirred for 2 days. The reactionmixture was diluted with ethyl acetate, the insoluble material wasfiltered off through celite, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.87 g, 87%).

¹H NMR (300 MHz, CDCl₃) δ 0.08 (3H, s), 0.10 (3H, s), 0.91 (9H, s), 1.01(3H, t, J=7.2), 1.14 (3H, t, J=7.2), 1.18-1.32 (9H, m), 1.63-1.81 (2H,m), 2.36 (2H, q, J=7.2), 2.30-2.43 (2H, m), 3.86 (1H, q, J=6.3), 3.97(2H, s), 7.10 (4H, s), 7.36-7.75 (6H, m), 7.57-7.66 (1H, m), 7.74 (1H,d, J=7.8)

444e)2-ethyl-3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.6 g), sodium hydrogencarbonate (2.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({1-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylpropoxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.87 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (12 mL). N,N′-carbonyldiimidazole (0.33 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.30 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was dissolvedin tetrahydrofuran (5 mL), tetrabutylammonium fluoride (2.5 mL and 1.0 Mtetrahydrofuran solution) were added, and the mixture was stirred for 24hr. The reaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.54 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.11-1.28 (9H, m), 1.49-1.66 (2H, m), 2.28 (2H, q, J=7.2), 2.51-2.59(2H, m), 3.62-3.74 (1H, m), 3.87 (2H, s), 4.78 (1H, d, J=5.4), 7.12 (2H,d, J=9.0), 7.17-7.33 (6H, m), 7.46-7.59 (2H, m), 7.61-7.74 (2H, m),12.38 (1H, br)

Example 445

3-[4-(1,1-dimethyl-2-oxopropoxy)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a solution of2-ethyl-3-[4-(2-hydroxy-1,1-dimethylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one(0.2 g) in dichloromethane (6 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.21 g),and the mixture was stirred for 2 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.18 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.05 (3H, t, J=7.2),1.48 (6H, s), 1.51-1.65 (2H, m), 2.21-2.32 (5H, m), 2.51-2.58 (2H, m),3.86 (2H, s), 6.89 (2H, d, J=9.0), 7.16-7.31 (6H, m), 7.46-7.59 (2H, m),7.61-7.72 (2H, m), 12.38 (1H, br)

Example 4462-(fluoromethyl)-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

446a)4′-{[1-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy]phenyl}-2-(fluoromethyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile

To a mixture of4′-[(1-{4-[(4-{[tert-butyl(diphenyl)silyl]oxy}cyclohexyl)oxy]phenyl}-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(2.33 g), sodium acetate (0.5 g) and acetic acid (20 mL) was addedbromine (0.31 mL), and the mixture was stirred at room temperature for 3hr. The solvent was evaporated from the reaction mixture under reducedpressure, and the residue was diluted with ethyl acetate. dilutionsolution was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was dissolved in tetrahydrofuran (20 mL), tetrabutylammoniumfluoride (1.0 M, 6 mL) was added, and the mixture was stirred at 80° C.for 12 hr. The solvent was evaporated from the reaction mixture underreduced pressure. The residue was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure.The residue was dissolved in methylene chloride (10 mL),tert-butyl(dimethyl)silyl trifluoromethanesulfonate (0.43 mL) and2,6-lutidine (0.32 mL) were added, and the mixture was stirred at 0° C.for 1 hr and at room temperature for 12 hr. The solvent was evaporatedfrom the reaction mixture under reduced pressure, and the residue wasdiluted with ethyl acetate. The diluted solution was washed with water,saturated aqueous sodium hydrogen carbonate solution and saturatedbrine, dried over anhydrous magnesium sulfate, and the solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound as a colorlessamorphous solid (0.18 g, 9%).

¹H NMR (300 MHz, CDCl₃) δ ppm 0.00 (s, 6H), 0.84 (s, 9H), 0.95 (t, J=7.23H), 1.42-1.75 (m, 8H), 1.87-1.98 (m, 2H), 2.57-2.71 (m, 2H), 3.68-3.82(m, 1H), 3.93 (s, 2H), 4.19-4.31 (m, 1H), 4.75-5.00 (m, 2H), 6.89-6.98(m, 2H), 7.05-7.12 (m, 2H), 7.30-7.43 (m, 6H), 7.51-7.58 (m, 1H),7.63-7.70 (m, 1H)

446b)2-(fluoromethyl)-3-{4-[(4-hydroxycyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogencarbonate (0.23 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-{[1-{4-[(4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)oxy]phenyl}-2-(fluoromethyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.18 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (2 mL). N,N′-carbonyldiimidazole (0.07 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (1 mL),tetrabutylammonium fluoride tetrahydrofuran solution (1 mol/L, 0.1 mL)was added, and the mixture was stirred at room temperature for 3 hr. Thesolvent was evaporated from the reaction mixture under reduced pressure.The residue was diluted with ethyl acetate, washed with water and thenwith saturated brine, and dried over anhydrous magnesium sulfate. Thesolvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.01 g, 6%).

¹H NMR (300 MHz, CDCl₃) δ ppm 1.06 (t, J=7.3, 3H), 1.33-1.65 (m, 5H),1.72-2.06 (m, 6H), 2.61-2.83 (m, 2H), 3.49-3.73 (m, 1H), 3.80-3.97 (m,3H), 4.25-4.37 (m, 1H), 4.83 (s, 1H), 4.99 (s, 1H), 6.85-6.98 (m, 2H),6.99-7.13 (m, 2H), 7.16-7.30 (m, 4H), 7.40-7.50 (m, 2H), 7.55-7.64 (m,1H), 7.71-7.80 (m, 1H), 8.04 (s, 1H)

Example 4472-ethyl-3-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

447a)4′-({2-ethyl-1-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1 g), ethyl 2-bromo-2-methylpropanoate (0.66 g), cesium carbonate (1.09g) and dimethylformamide (15 mL) were stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL), methylmagnesium bromide (3.0 M,0.6 mL) was added, and the mixture was stirred at −78° C. for 2 hr androom temperature for 12 hr. The solvent was evaporated from the reactionmixture under reduced pressure. The residue was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure, obtained the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.36 g, 30%).

¹H NMR (300 MHz, CDCl₃) δ ppm 1.01 (t, J=7.4, 3H), 1.15 (t, J=7.5, 3H),1.31 (s, 6H), 1.34 (s, 6H), 1.64-1.80 (m, 2H), 2.37 (q, J=7.5, 2H),2.64-2.71 (m, 3H), 3.98 (s, 2H), 7.09-7.19 (m, 4H), 7.35-7.50 (m, 6H),7.57-7.64 (m, 1H), 7.73 (dd, J=7.7, 0.9, 1H)

447b)2-ethyl-3-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.38 g), sodium hydrogencarbonate (0.55 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-({2-ethyl-1-[4-(2-hydroxy-1,1,2-trimethylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(0.36 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.16 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with saturated aqueouspotassium hydrogen sulfate solution and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.14 g, 35%).

¹H NMR (300 MHz, DMSO-d₆) δ ppm 0.90 (t, J=7.4, 3H), 1.01-1.08 (m, 4H),1.26 (d, J=1.3, 20H), 1.51-1.66 (m, 2H), 2.28 (q, J=7.5, 2H), 3.53-3.67(m, 1H), 3.87 (s, 2H), 4.45 (s, 1H), 7.09-7.15 (m, 2H), 7.19-7.31 (m,6H), 7.47-7.58 (m, 2H), 7.63-7.72 (m, 2H)

Example 448

5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a solution of5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.10 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.022 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.09 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.5), 1.42 (6H, s), 1.58-1.72(2H, m), 2.11 (3H, s), 2.67 (2H, t, J=7.5), 3.01 (2H, s), 5.28 (2H, s),6.69 (1H, d, J=8.1), 6.97 (1H, d, J=8.1), 7.06-7.13 (3H, m), 7.23-7.30(3H, m), 7.31-7.44 (2H, m), 7.46-7.50 (1H, m)

Example 449

5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a solution of5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.10 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.023 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.05 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.5), 1.29 (6H, d, J=6.0),1.57-1.73 (2H, m), 2.12 (3H, s), 2.68 (2H, t, J=7.5), 4.56-4.70 (1H, m),5.30 (2H, s), 6.93 (2H, d, J=8.7), 7.12 (2H, d, J=8.1), 7.21 (2H, d,J=8.7), 7.25-7.46 (5H, m), 7.50 (1H, d, J=7.5)

Example 4503-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-isopropoxyphenyl)-6-methyl-2-propylpyrimidin-4(3H)-one

450a)3′-fluoro-4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of 6-methyl-2-propylpyrimidin-4(3H)-one (2.0 g) and4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (4.4 g) inacetonitrile (50 mL) was added potassium carbonate (3.6 g), and themixture was stirred at 50° C. for 12 hr. The insoluble material wasfiltered off, the filtrate was concentrated, and the residue waspurified by silica gel column chromatography to give the title compound(1.4 g, 29%) as a colorless viscous substance.

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.5), 1.68-1.83 (2H, m), 2.29(3H, s), 2.66 (2H, t, J=7.5), 5.39 (2H, s), 6.29 (1H, s), 7.08-7.17 (1H,m), 7.24-7.36 (2H, m), 7.43-7.52 (2H, m), 7.61-7.70 (1H, m), 7.77 (1H,d, J=7.8)

450b)4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile

To a solution of3′-fluoro-4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.4 g) and sodium acetate (0.32 g) in acetic acid (20 mL) was addedbromine (0.2 mL), and the mixture was stirred at 70° C. for 2 hr. Thereaction mixture was diluted with toluene and concentrated under reducedpressure. The residue was dissolved in ethyl acetate, 1 M aqueous sodiumthiosulfate solution, washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound (0.65 g, 38%) as a colorless solid.

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.2), 1.60-1.74 (2H, m), 2.42(3H, s), 2.72 (2H, t, J=7.2), 5.39 (2H, s), 7.12 (1H, t, J=8.1), 7.38(1H, d, J=7.8), 7.50-7.61 (3H, m), 7.75-7.85 (1H, m), 7.97 (1H, d,J=7.8)

450c)3′-fluoro-4′-{[5-(4-isopropoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.65 g) and 4-isopropoxyphenylboronic acid (0.40 g) in 1,4-dioxane (16mL) were added 2 M aqueous cesium carbonate solution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.06 g), andthe mixture was stirred at 90° C. for 12 hr under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonatesolution and saturated brine in this order, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.49 g, 67%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃) δ 1.04 (3H, t, J=7.2), 1.35 (6H, d, J=6.0),1.72-1.87 (2H, m), 2.25 (3H, s), 2.71 (2H, t, J=7.2), 4.50-4.64 (1H, m),5.41 (2H, s), 6.93 (2H, d, J=8.7), 7.21-7.34 (5H, m), 7.43-7.52 (2H, m),7.61-7.70 (1H, m), 7.77 (1H, d, J=6.9)

450d)3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-isopropoxyphenyl)-6-methyl-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-{[5-(4-isopropoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.49 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.24 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.39 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.2), 1.28 (6H, d, J=6.0),1.58-1.74 (2H, m), 2.14 (3H, s), 2.68 (2H, t, J=7.2), 4.57-4.69 (1H, m),5.34 (2H, s), 6.92 (2H, d, J=8.4), 7.00-7.14 (2H, m), 7.16-7.29 (3H, m),7.50-7.64 (2H, m), 7.65-7.75 (2H, m), 12.48 (1H, s)

Example 451

3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-isopropoxyphenyl)-6-methyl-2-propylpyrimidin-4(3H)-onepotassium salt

To a solution of3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-isopropoxyphenyl)-6-methyl-2-propylpyrimidin-4(3H)-one(0.36 g) in ethanol (10 mL) was added 8 M potassium hydroxide solution(0.081 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.33 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.2), 1.28 (6H, d, J=6.0),1.60-1.78 (2H, m), 2.13 (3H, s), 2.70 (2H, t, J=7.2), 4.57-4.69 (1H, m),5.31 (2H, s), 6.88-6.95 (3H, m), 7.07-7.23 (4H, m), 7.30-7.47 (3H, m),7.50-7.56 (1H, m)

Example 4522-butyl-5-[hydroxy(phenyl)methyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

452a)4′-[(2-butyl-4-methyl-6-oxo-5-vinylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.9 g), tributyl(vinyl)tin (2.1 g) and lithium chloride (0.55 g) inN,N-dimethylformamide (30 mL) was addeddichlorobis(triphenylphosphine)palladium (0.15 g), and the mixture wasstirred at 90° C. for 12 hr under an argon atmosphere. The reactionmixture was diluted with ethyl acetate, 15% aqueous potassium fluoridesolution was added, and the mixture was stirred for 2 hr. The insolublematerial was filtered off through celite, and the organic layer of thefiltrate was separated, washed with 1 M hydrochloric acid, saturatedaqueous sodium hydrogen carbonate solution and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.1 g,63%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.2), 1.31-1.46 (2H, m),1.61-1.75 (2H, m), 2.43 (3H, s), 2.64 (2H, t, J=7.2), 5.38 (2H, s), 5.53(1H, dd, J=2.4, 12.0), 6.29 (1H, dd, J=2.4, 17.4), 6.68 (1H, dd, J=12.0,17.4), 7.26-7.31 (2H, m), 7.40-7.56 (4H, m), 7.60-7.68 (1H, m), 7.76(1H, d, J=8.4)

452b)4′-[(2-butyl-5-formyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(2-butyl-4-methyl-6-oxo-5-vinylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.91 g) and sodium periodate (2.56 g) in acetone (10 mL)-acetonitrile(10 mL)-water (10 mL) was added osmium tetroxide (0.9 g, 7%polymer-bound catalyst), and the mixture was stirred for 4 hr. Theinsoluble material was filtered off through celite, and the filtrate wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid, saturatedaqueous sodium hydrogen carbonate solution and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow oil (0.66 g,71%).

¹H NMR (300 MHz, CDCl₃) δ 0.91 (3H, t, J=7.2), 1.29-1.46 (2H, m),1.58-1.79 (2H, m), 2.67 (3H, s), 2.75 (2H, t, J=7.2), 5.39 (2H, s),7.29-7.36 (2H, m), 7.42-7.52 (2H, m), 7.56 (2H, d, J=8.4), 7.61-7.69(1H, m), 7.77 (1H, d, J=7.8), 10.50 (1H, s)

452c)4′-{[2-butyl-5-[hydroxy(phenyl)methyl]-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(2-butyl-5-formyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.66 g) in tetrahydrofuran (10 mL) was added phenylmagnesium bromide(1.0 mL, 1 M tetrahydrofuran solution) at −78° C., and the mixture wasallowed to warm to 0° C. over 3 hr. A saturated aqueous ammoniumchloride solution was added to the reaction mixture, and the mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid, saturatedaqueous sodium hydrogen carbonate solution and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a pale-yellow oil (0.36 g,46%).

¹H NMR (300 MHz, CDCl₃) δ 0.90 (3H, t, J=7.2), 1.30-1.46 (2H, m),1.62-1.77 (2H, m), 2.42 (3H, s), 2.68 (2H, t, J=7.2), 5.20-5.45 (2H, m),5.09 (1H, d, J=10.8), 5.82 (1H, d, J=10.8), 7.18-7.29 (3H, m), 7.30-7.39(2H, m), 7.40-7.55 (6H, m), 7.60-7.69 (1H, m), 7.76 (1H, d, J=7.2)

452d)2-butyl-5-[hydroxy(phenyl)methyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-5-[hydroxy(phenyl)methyl]-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.36 g) was added, and the mixture was stirred at 90° C. for 24 hr. Themixture was allowed to cool to room temperature, water was added to thereaction mixture, and the precipitated solid was collected byfiltration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.13 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.12 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.19 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.80 (3H, t, J=7.2), 1.18-1.33 (2H, m),1.46-1.60 (2H, m), 2.13 (3H, s), 2.59-2.69 (2H, m), 5.26-5.50 (2H, m),5.82 (1H, d, J=5.1), 6.23 (1H, d, J=5.1), 7.15-7.40 (9H, m), 7.48-7.61(2H, m), 7.63-7.74 (2H, m)

Example 453

5-benzoyl-2-butyl-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

To a solution of2-butyl-5-[hydroxy(phenyl)methyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.1 g) in dichloromethane (4 mL) was added1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one (0.12 g),and the mixture was stirred for 2 hr. Ethyl acetate, water and sodiumthiosulfate were added to the reaction mixture, and the mixture wasstirred for 30 min and extracted with ethyl acetate. The organic layerwas washed with saturated brine, and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.07 g, 70%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.2), 1.25-1.39 (2H, m),1.54-1.69 (2H, m), 2.11 (3H, s), 2.75 (2H, t, J=7.2), 5.34 (2H, s), 7.25(2H, d, J=8.1), 7.33 (2H, d, J=8.1), 7.48-7.61 (4H, m), 7.64-7.74 (3H,m), 7.85 (2H, d, J=7.2)

Example 454

2-butyl-5-[hydroxy(phenyl)methyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-onepotassium salt

To a solution of2-butyl-5-[hydroxy(phenyl)methyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.1 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.024 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.046 g, 43%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81 (3H, t, J=7.2), 1.21-1.35 (2H, m),1.47-1.63 (2H, m), 2.12 (3H, s), 2.59-2.74 (2H, m), 5.23 (1H, d,J=15.9), 5.42 (1H, d, J=15.9), 5.84 (1H, s), 6.24 (1H, s), 7.10 (2H, d,J=7.8), 7.16-7.23 (1H, m), 7.26-7.46 (9H, m), 7.50 (1H, d, J=7.5)

Example 4556-ethyl-5-(morpholin-4-ylmethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

455a)4′-[(4-ethyl-6-oxo-2-propyl-5-vinylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(10 g), tributyl(vinyl)tin (10 g) and lithium chloride (2.9 g) inN,N-dimethylformamide (200 mL) was addeddichlorobis(triphenylphosphine)palladium (0.80 g), and the mixture wasstirred at 90° C. for 12 hr under an argon atmosphere. The reactionmixture was diluted with ethyl acetate, 15% aqueous potassium fluoridesolution was added, and the mixture was stirred for 2 hr. The insolublematerial was filtered off through celite, and the organic layer of thefiltrate was separated, washed with 1 M hydrochloric acid, saturatedaqueous sodium hydrogen carbonate solution and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (5.9 g,68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.2), 1.18 (3H, t, J=7.5),1.60-1.74 (2H, m), 2.65-2.74 (4H, m), 5.38 (2H, s), 5.43 (1H, dd, J=3.8,12.6), 6.32 (1H, dd, J=3.0, 17.4), 6.69 (1H, dd, J=12.6, 17.4), 7.30(2H, d, J=8.4), 7.53-7.65 (4H, m), 7.75-7.83 (1H, m), 7.94 (1H, d,J=8.1)

455b)4′-[(4-ethyl-5-formyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

To a solution of4′-[(4-ethyl-6-oxo-2-propyl-5-vinylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(5.9 g) and sodium periodate (16 g) in acetone (100 mL)-acetonitrile(100 mL)-water (100 mL) was added osmium tetroxide (5 g, 7%polymer-bound catalyst), and the mixture was stirred for 4 hr. Theinsoluble material was filtered off through celite, and the filtrate wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid, saturatedaqueous sodium hydrogen carbonate solution and saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (3.8 g,64%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.2), 1.25 (3H, t, J=7.5),1.71-1.90 (2H, m), 2.74 (2H, t, J=7.2), 3.05 (2H, q, J=7.5), 5.38 (2H,s), 7.30-7.37 (2H, m), 7.42-7.52 (2H, m), 7.53-7.60 (2H, m), 7.61-7.70(1H, m), 7.77 (1H, d, J=7.2), 10.49 (1H, s)

455c)4′-{[4-ethyl-5-(morpholin-4-ylmethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(4-ethyl-5-formyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) and morpholine (0.17 mL) in acetic acid (10 mL) was added sodiumtriacetoxyborohydride (0.41 g), and the mixture was stirred for 12 hr.The reaction mixture was diluted with ethyl acetate, washed withsaturated aqueous sodium hydrogen carbonate solution and saturatedbrine, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified by silicagel column chromatography to give the title compound as a pale-yellowoil (0.21 g, 35%).

¹H NMR (300 MHz, CDCl₃) δ 0.88-1.07 (3H, m), 1.16-1.38 (3H, m),1.70-1.87 (2H, m), 2.44-2.60 (4H, m), 2.60-2.81 (4H, m), 3.50 (2H, s),3.58-3.81 (4H, m), 5.35 (2H, s), 7.22-7.36 (2H, m), 7.37-7.59 (4H, m),7.59-7.71 (1H, m), 7.71-7.82 (1H, m)

455d)6-ethyl-5-(morpholin-4-ylmethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.54 g), sodium hydrogencarbonate (0.77 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(morpholin-4-ylmethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.21 g) was added, and the mixture was stirred at 90° C. for 24 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.11 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.10 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.14 g, 61%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.86 (3H, t, J=7.2), 1.19 (3H, t, J=7.2),1.54-1.70 (2H, m), 2.38 (4H, br), 2.56-2.68 (4H, m), 3.41 (2H, s), 3.53(4H, br), 5.31 (2H, s), 7.17 (2H, d, J=8.4), 7.29 (2H, d, J=8.4),7.47-7.60 (2H, m), 7.61-7.73 (2H, m)

Example 4566-ethyl-5-(4-methoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

456a)4′-{[4-ethyl-5-(4-methoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 4-methoxyphenylboronic acid (0.26 g) in 1,4-dioxane (15 mL)were added 2 M aqueous cesium carbonate solution (3 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), andthe mixture was stirred at 90° C. for 12 hr under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonatesolution and saturated brine in this order, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.48 g, 91%) as a colorless solid.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.5), 1.18 (3H, t, J=7.2),1.74-1.89 (2H, m), 2.48 (2H, q, J=7.2), 2.73 (2H, t, J=7.5), 3.83 (3H,s), 5.37 (2H, s), 6.98 (2H, d, J=9.0), 7.22-7.28 (2H, m), 7.33-7.39 (2H,m), 7.40-7.56 (4H, m), 7.60-7.68 (1H, m), 7.76 (1H, d, J=7.5)

456b)6-ethyl-5-(4-methoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.2 g), sodium hydrogencarbonate (1.7 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(4-methoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.48 g) was added, and the mixture was stirred at 90° C. for 24 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.44 g, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.2), 1.10 (3H, t, J=7.2),1.57-1.73 (2H, m), 2.36 (2H, q, J=7.2), 2.68 (2H, t, J=7.2), 3.79 (3H,s), 5.34 (2H, s), 6.97 (2H, d, J=9.0), 7.16-7.35 (6H, m), 7.48-7.61 (2H,m), 7.63-7.74 (2H, m), 12.40 (1H, br)

Example 4576-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(trifluoromethoxy)phenyl]pyrimidin-4(3H)-one

457a)4′-{[4-ethyl-6-oxo-2-propyl-5-[4-(trifluoromethoxy)phenyl]pyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) and 4-trifluoromethoxyphenylboronic acid (0.35 g) in 1,4-dioxane(15 mL) were added 2 M aqueous cesium carbonate solution (3 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), andthe mixture was stirred at 90° C. for 12 hr under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonatesolution and saturated brine in this order, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.56 g, 95%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃) δ 1.03 (3H, t, J=7.5), 1.19 (3H, t, J=7.5),1.74-1.92 (2H, m), 2.46 (2H, q, J=7.5), 2.75 (2H, t, J=7.5), 5.37 (2H,s), 7.22-7.30 (2H, m), 7.36 (4H, m), 7.42-7.58 (4H, m), 7.59-7.69 (1H,m), 7.76 (1H, d, J=7.8)

457b)6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(trifluoromethoxy)phenyl]pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-6-oxo-2-propyl-5-[4-(trifluoromethoxy)phenyl]pyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.56 g) was added, and the mixture was stirred at 90° C. for 24 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.39 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.2), 1.11 (3H, t, J=7.2),1.58-1.74 (2H, m), 2.35 (2H, q, J=7.5), 2.70 (2H, t, J=7.2), 5.35 (2H,s), 7.23-7.35 (4H, m), 7.36-7.47 (4H, m), 7.47-7.61 (2H, m), 7.63-7.73(2H, m), 12.41 (1H, br)

Example 4586-ethyl-5-(2-fluoro-4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

458a)4′-{[4-ethyl-5-(2-fluoro-4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) and 2-fluoro-4-isopropoxyphenylboronic acid (0.34 g) in1,4-dioxane (15 mL) were added 2 M aqueous cesium carbonate solution (3mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05g), and the mixture was stirred at 90° C. for 12 hr under an argonatmosphere. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off through celite. The filtrate waswashed with 1 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine in this order, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.35 g, 59%) as a colorlessamorphous solid.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.2), 1.17 (3H, t, J=7.2), 1.35(6H, d, J=6.3), 1.73-1.59 (2H, m), 2.36-2.51 (2H, m), 2.73 (2H, t,J=7.2), 4.47-4.60 (1H, m), 5.38 (2H, s), 6.62-6.76 (2H, m), 7.12-7.26(1H, m), 7.31-7.39 (2H, m), 7.40-7.57 (4H, m), 7.60-7.68 (1H, m), 7.76(1H, d, J=7.8)

458b)6-ethyl-5-(2-fluoro-4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.80 g), sodium hydrogencarbonate (1.1 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(2-fluoro-4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.35 g) was added, and the mixture was stirred at 90° C. for 24 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.17 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.25 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.2), 1.09 (3H, t, J=7.2),1.29 (6H, d, J=6.0), 1.56-1.74 (2H, m), 2.31 (2H, q, J=7.2), 2.64-2.76(2H, m), 4.59-4.74 (1H, m), 5.24-5.43 (2H, m), 6.77-6.90 (2H, m),7.15-7.36 (5H, m), 7.47-7.61 (2H, m), 7.63-7.74 (2H, m), 12.39 (1H, br)

Example 4596-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-propoxyphenyl)-2-propylpyrimidin-4(3H)-one

459a)4′-{[4-ethyl-6-oxo-5-(4-propoxyphenyl)-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) and 4-propoxyphenylboronic acid (0.31 g) in 1,4-dioxane (15 mL)were added 2 M aqueous cesium carbonate solution (3 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g), andthe mixture was stirred at 90° C. for 12 hr under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonatesolution and saturated brine in this order, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.52 g, 93%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃) δ 0.96-1.08 (6H, m), 1.18 (3H, t, J=7.2),1.72-1.90 (4H, m), 2.48 (2H, q, J=7.2), 2.73 (2H, t, J=7.2), 3.95 (2H,t, J=6.6), 5.37 (2H, s), 6.95 (2H, d, J=8.7), 7.23 (2H, d, J=8.7),7.32-7.40 (2H, m), 7.40-7.57 (4H, m), 7.60-7.68 (1H, m), 7.76 (1H, d,J=6.9)

459b)6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-propoxyphenyl)-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-6-oxo-5-(4-propoxyphenyl)-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.52 g) was added, and the mixture was stirred at 90° C. for 24 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.26 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.24 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.39 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.2), 0.99 (3H, t, J=7.2),1.10 (3H, t, J=7.2), 1.57-1.82 (4H, m), 2.36 (2H, q, J=7.2), 2.68 (2H,t, J=7.2), 3.96 (2H, t, J=7.2), 5.34 (2H, s), 6.96 (2H, d, J=8.7),7.13-7.35 (6H, m), 7.49-7.61 (2H, m), 7.63-7.74 (2H, m), 12.40 (1H, br)

Example 4606-ethyl-5-(3-fluoro-4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

460a)4′-{[4-ethyl-5-(3-fluoro-4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) and 3-fluoro-4-isopropoxyphenylboronic acid (0.34 g) in1,4-dioxane (15 mL) were added 2 M aqueous cesium carbonate solution (3mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05g), and the mixture was stirred at 90° C. for 12 hr under an argonatmosphere. The reaction mixture was diluted with ethyl acetate, and theinsoluble material was filtered off through celite. The filtrate waswashed with 1 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated brine in this order, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound (0.53 g, 91%) as a colorlessamorphous solid.

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.2), 1.19 (3H, t, J=7.2), 1.38(6H, d, J=6.0), 1.74-1.89 (2H, m), 2.48 (2H, q, J=7.2), 2.73 (2H, t,J=7.2), 4.49-4.63 (1H, m), 5.36 (2H, s), 6.97-7.10 (3H, m), 7.31-7.39(2H, m), 7.41-7.57 (4H, m), 7.60-7.68 (1H, m), 7.76 (1H, d, J=7.8)

460b)6-ethyl-5-(3-fluoro-4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.3 g), sodium hydrogencarbonate (1.8 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(3-fluoro-4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.53 g) was added, and the mixture was stirred at 90° C. for 24 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.47 g, 79%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.2), 1.11 (3H, t, J=7.2),1.31 (6H, d, J=6.0), 1.57-1.74 (2H, m), 2.37 (2H, q, J=7.2), 2.68 (2H,t, J=7.2), 4.60-4.73 (1H, m), 5.34 (2H, s), 6.97-7.06 (1H, m), 7.11-7.36(6H, m), 7.49-7.61 (2H, m), 7.63-7.74 (2H, m), 12.40 (1H, br)

Example 461

6-ethyl-5-(4-methoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a solution of6-ethyl-5-(4-methoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.31 g) in ethanol (10 mL) was added 8 M potassium hydroxide solution(0.073 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.33 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.2), 1.10 (3H, t, J=7.2),1.61-1.77 (2H, m), 2.35 (2H, q, J=7.2), 2.71 (2H, t, J=7.2), 3.79 (3H,s), 5.30 (2H, s), 6.97 (2H, d, J=8.7), 7.13 (2H, d, J=8.4), 7.20 (2H, d,J=8.7), 7.26-7.47 (5H, m), 7.51 (1H, d, J=7.5)

Example 462

6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(trifluoromethoxy)phenyl]pyrimidin-4(3H)-onepotassium salt

To a solution of6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(trifluoromethoxy)phenyl]pyrimidin-4(3H)-one(0.30 g) in ethanol (10 mL) was added 8 M potassium hydroxide solution(0.065 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.31 g, 96%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.2), 1.11 (3H, t, J=7.5),1.61-1.78 (2H, m), 2.34 (2H, q, J=7.5), 2.74 (2H, t, J=7.2), 5.31 (2H,s), 7.15 (2H, d, J=8.1), 7.25-7.54 (10H, m)

Example 463

6-ethyl-5-(2-fluoro-4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a solution of6-ethyl-5-(2-fluoro-4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.19 g) in ethanol (10 mL) was added 8 M potassium hydroxide solution(0.047 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.15 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.2), 1.08 (3H, t, J=7.5),1.29 (6H, d, J=6.0), 1.59-1.78 (2H, m), 2.30 (2H, q, J=7.5), 2.62-2.82(2H, m), 4.57-4.75 (1H, m), 5.19-5.40 (2H, m), 6.73-6.90 (2H, m), 7.12(2H, d, J=8.1), 7.16-7.25 (1H, m), 7.25-7.46 (5H, m), 7.50 (1H, d,J=7.5)

Example 464

6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-propoxyphenyl)-2-propylpyrimidin-4(3H)-onepotassium salt

To a solution of6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-propoxyphenyl)-2-propylpyrimidin-4(3H)-one(0.31 g) in ethanol (2 mL) was added 8 M potassium hydroxide solution(0.069 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.32 g, 97%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-1.04 (6H, m), 1.10 (3H, t, J=7.2),1.60-1.83 (4H, m), 2.36 (2H, q, J=7.2), 2.71 (2H, t, J=7.5), 3.96 (2H,t, J=6.6), 5.29 (2H, s), 6.95 (2H, d, J=8.7), 7.13 (2H, d, J=8.7), 7.19(2H, d, J=8.7), 7.25-7.47 (5H, m), 7.50 (1H, d, J=7.5)

Example 465

6-ethyl-5-(3-fluoro-4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a solution of6-ethyl-5-(3-fluoro-4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.32 g) in ethanol (10 mL) was added 8 M potassium hydroxide solution(0.078 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.32 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.2), 1.11 (3H, t, J=7.2),1.31 (6H, d, J=6.0), 1.61-1.76 (2H, m), 2.37 (2H, q, J=7.2), 2.72 (2H,t, J=7.2), 4.59-4.73 (1H, m), 5.30 (2H, s), 6.99-7.06 (1H, m), 7.10-7.23(4H, m), 7.26-7.46 (5H, m), 7.48-7.54 (1H, m)

Example 4666-ethyl-5-(morpholin-4-ylcarbonyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

466a)1-[(2′-cyanobiphenyl-4-yl)methyl]-4-ethyl-6-oxo-2-propyl-1,6-dihydropyrimidine-5-carboxylicacid

To a solution of4′-[(4-ethyl-5-formyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g), sodium dihydrogen phosphate (0.93 g) and 2-methyl-2-butene (4mL) in tert-butyl alcohol (10 mL)—water (8 mL) was added sodium chlorite(0.7 g), and the mixture was stirred at room temperature for 1 hr. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid and then with saturated brine, and dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure to give the title compound as a colorless solid (0.53 g, 100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.2), 1.17 (3H, t, J=7.2),1.63-1.73 (2H, m), 2.60-2.82 (4H, m), 5.40 (2H, s), 7.35 (2H, d, J=8.4),7.53-7.66 (4H, m), 7.74-7.56 (1H, m), 7.95 (1H, d, J=7.8), 13.52 (1H,br)

466b)4′-{[4-ethyl-5-(morpholin-4-ylcarbonyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of1-[(2′-cyanobiphenyl-4-yl)methyl]-4-ethyl-6-oxo-2-propyl-1,6-dihydropyrimidine-5-carboxylicacid (0.21 g), morpholine (0.07 g) and triethylamine (0.22 mL) inN,N-dimethylformamide were addedN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.15 g)and 1-hydroxybenzotriazole monohydrate (0.12 g), and the mixture wasstirred for 12 hr. The reaction mixture was diluted with ethyl acetate,washed with 1 M hydrochloric acid and then with saturated brine, anddried over anhydrous sodium sulfate. The solvent was evaporated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.22 g,89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.99 (3H, t, J=7.5), 1.27 (3H, t, J=7.5),1.68-1.83 (2H, m), 2.57 (2H, q, J=7.5), 2.65-2.74 (2H, m), 3.25-3.47(2H, m), 3.54-3.65 (1H, m), 3.68-3.93 (5H, m), 5.33 (2H, s), 7.30 (2H,d, J=8.1), 7.41-7.56 (4H, m), 7.60-7.69 (1H, m), 7.76 (1H, d, J=7.5)

466c)6-ethyl-5-(morpholin-4-ylcarbonyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.56 g), sodium hydrogencarbonate (0.79 g) and dimethyl sulfoxide (4 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(morpholin-4-ylcarbonyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.22 g) was added, and the mixture was stirred at 90° C. for 24 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.12 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.10 g, 39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.5), 1.16 (3H, t, J=7.2),1.55-1.72 (2H, m), 2.42 (2H, q, J=7.5), 2.69 (2H, t, J=7.5), 3.15-3.40(3H, m), 3.40-3.71 (5H, m), 5.32 (2H, s), 7.22 (2H, d, J=8.1), 7.31 (2H,d, J=8.1), 7.48-7.61 (2H, m), 7.48-7.61 (2H, m), 7.62-7.74 (2H, m),12.41 (1H, br)

Example 4676-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(6-isopropoxypyridin-3-yl)-2-propylpyrimidin-4(3H)-one

467a)4′-{[4-ethyl-5-(6-isopropoxypyridin-3-yl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

To a solution of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.49 g) and 2-isopropoxy-3-pyridylboronic acid (0.43 g) in 1,4-dioxane(20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.04 g), andthe mixture was stirred at 90° C. for 12 hr under an argon atmosphere.The reaction mixture was diluted with ethyl acetate, and the insolublematerial was filtered off through celite. The filtrate was washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonatesolution and saturated brine in this order, and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound (0.39 g, 70%) as a colorless amorphous solid.

¹H NMR (300 MHz, CDCl₃) δ 1.04 (3H, t, J=7.2), 1.21 (3H, t, J=7.5), 1.36(6H, d, J=6.0), 1.75-1.90 (2H, m), 2.51 (2H, q, J=7.5), 2.68-2.78 (2H,m), 5.26-5.37 (1H, m), 5.40 (2H, s), 6.74 (1H, d, J=9.0), 7.20-7.35 (3H,m), 7.44-7.52 (2H, m), 7.55-7.70 (2H, m), 7.78 (1H, d, J=8.4), 8.07 (1H,d, J=2.1)

467b)6-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(6-isopropoxypyridin-3-yl)-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.89 g), sodium hydrogencarbonate (1.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(6-isopropoxypyridin-3-yl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.39 g) was added, and the mixture was stirred at 90° C. for 24 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.18 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.17 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.23 g, 54%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.5), 1.13 (3H, t, J=7.5),1.30 (6H, d, J=6.3), 1.61-1.78 (2H, m), 2.39 (2H, q, J=7.5), 2.71 (2H,t, J=7.5), 5.20-5.32 (1H, m), 5.35 (2H, s), 6.78 (1H, d, J=8.4),7.01-7.14 (2H, m), 7.22-7.28 (1H, m), 7.49-7.76 (5H, m), 8.03 (1H, s),12.49 (1H, br)

Example 468

6-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(6-isopropoxypyridin-3-yl)-2-propylpyrimidin-4(4H)-onepotassium salt

To a solution of6-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(6-isopropoxypyridin-3-yl)-2-propylpyrimidin-4(4H)-one(0.16 g) in ethanol (5 mL) was added 8 M potassium hydroxide solution(0.036 mL), and the solvent was evaporated under reduced pressure. Theresidue was triturated with diisopropyl ether to give the title compoundas a colorless solid (0.14 g, 82%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.2), 1.13 (3H, t, J=7.2),1.31 (6H, d, J=6.3), 1.64-1.80 (2H, m), 2.39 (2H, q, J=7.2), 2.73 (2H,t, J=7.2), 5.21-5.35 (3H, m), 6.78 (1H, d, J=8.7), 6.91-7.00 (1H, m),7.07-7.20 (2H, m), 7.29-7.48 (3H, m), 7.51-7.57 (1H, m), 7.58-7.64 (1H,m), 8.04 (1H, s)

Example 469

6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (1.7 g), sodium hydrogencarbonate (2.5 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) was added, and the mixture was stirred at 90° C. for 24 hr. Thereaction mixture was allowed to cool to room temperature, water wasadded to the reaction mixture, and the precipitated solid was collectedby filtration. The obtained solid was dissolved in ethyl acetate. Thesolution was washed with saturated brine and dried over anhydrous sodiumsulfate. The solvent was evaporated and the residue was dissolved intetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.35 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.33 mL) were added, and the mixturewas stirred at room temperature for 30 min. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid and thenwith saturated brine, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography to give the title compound as acolorless solid (0.26 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (3H, t, J=7.5), 1.50-1.67 (2H, m), 2.20(3H, s), 2.62 (2H, t, J=7.5), 5.31 (2H, s), 6.26 (1H, s), 7.19 (2H, d,J=8.4), 7.30 (2H, d, J=8.4), 7.48-7.61 (2H, m), 7.63-7.73 (2H, m), 12.40(1H, br)

Example 4703-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-isopropoxyphenyl)-6-methyl-2-propylpyrimidin-4(3H)-one

470a)4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-2′-fluorobiphenyl-2-carbonitrile

To a mixture of2′-fluoro-4′-[(4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.78 g), sodium acetate (0.19 g) and acetic acid (10 mL) was addedbromine (0.12 mL), and the mixture was stirred at room temperature for 3hr. The solvent was evaporated from the reaction mixture under reducedpressure, and the residue was diluted with ethyl acetate. The dilutedsolution was washed with water, saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound as a colorless amorphous solid (0.54 g, 57%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.4, 3H), 1.68-1.85 (m, 2H), 2.50(s, 3H), 2.61-2.71 (m, 2H), 5.36 (s, 2H), 7.01-7.13 (m, 2H), 7.35-7.53(m, 3H), 7.62-7.70 (m, 1H), 7.77 (d, J=8.3, 1H)

470b)2′-fluoro-4′-{[5-(4-isopropoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-2′-fluorobiphenyl-2-carbonitrile(0.54 g), (4-isopropoxyphenyl)boronic acid (0.33 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution(5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.6 g, 99%).

¹H NMR (300 MHz, CDCl₃) δ 1.03 (t, J=7.4, 3H), 1.35 (d, J=6.1, 6H),1.72-1.87 (m, 2H), 2.25 (s, 2H), 2.50 (s, 1H), 2.68-2.75 (m, 2H),4.50-4.64 (m, 1H), 5.35 (s, 2H), 6.89-7.02 (m, 2H), 7.05-7.16 (m, 2H),7.24 (d, J=9.8, 2H), 7.36-7.44 (m, 1H), 7.44-7.53 (m, 2H), 7.61-7.69 (m,1H), 7.74-7.80 (m, 1H)

470c)3-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-isopropoxyphenyl)-6-methyl-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.72 g), sodium hydrogencarbonate (1.02 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,2′-fluoro-4′-{[5-(4-isopropoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.6 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (8 mL). N,N′-carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.3 g, 45%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.6, 3H), 1.29 (d, J=6.1, 6H),1.57-1.72 (m, 2H), 2.13 (s, 3H), 2.63-2.71 (m, 2H), 4.57-4.70 (m, 1H),5.35 (s, 2H), 6.90-6.97 (m, 2H), 7.01-7.16 (m, 2H), 7.19-7.25 (m, 2H),7.29-7.40 (m, 1H), 7.47-7.56 (m, 1H), 7.62-7.66 (m, 1H), 7.68-7.75 (m,2H), 12.62 (s, 1H)

Example 471

3-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-isopropoxyphenyl)-6-methyl-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of3-{[2-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(4-isopropoxyphenyl)-6-methyl-2-propylpyrimidin-4(3H)-one(0.24 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (4.4 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.25 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.8, 3H), 1.29 (d, J=6.1, 6H),1.61-1.75 (m, 2H), 2.13 (s, 3H), 2.63-2.76 (m, 2H), 4.56-4.72 (m, 1H),5.33 (s, 2H), 6.89-7.01 (m, 4H), 7.16-7.26 (m, 4H), 7.37-7.45 (m, 2H),7.73-7.78 (m, 1H)

Example 4725-(1H-indol-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

472a)4′-{[5-(1H-indol-5-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.61 g), 1H-indol-5-ylboronic acid (0.33 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution(5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.41 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.4, 3H), 1.72-1.87 (m, 2H), 2.25(s, 3H), 2.69-2.78 (m, 2H), 5.41 (s, 2H), 6.47-6.55 (m, 1H), 7.04-7.14(m, 2H), 7.24-7.68 (m, 9H), 7.75 (d, J=7.4, 1H), 8.51 (s, 1H)

472b)5-(1H-indol-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogencarbonate (0.75 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[5-(1H-indol-5-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.41 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (40 mL). N,N′-carbonyldiimidazole (0.22 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.09 g, 20%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.61-1.76 (m, 2H), 2.13(s, 3H), 2.66-2.73 (m, 2H), 5.32 (s, 2H), 6.43 (s, 1H), 6.97-7.04 (m,1H), 7.14 (d, J=8.3, 2H), 7.27-7.47 (m, 8H), 7.49-7.54 (m, 1H), 8.32 (s,1H), 11.19 (s, 1H)

472c)5-(1H-indol-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-(1H-indol-5-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.09 g) and ethanol (2 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (2 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.07 g, 79%).

¹H NMR (300 MHz, CDCl₃) δ 0.95 (t, J=7.4, 3H), 1.64-1.80 (m, 2H), 2.13(s, 3H), 2.60-2.68 (m, 2H), 5.21 (s, 2H), 6.42 (s, 1H), 6.93 (d, J=8.3,1H), 7.04-7.07 (m, 1H), 7.09-7.21 (m, 5H), 7.24-7.35 (m, 3H), 7.39 (s,1H), 7.44-7.51 (m, 1H), 8.59 (s, 1H)

Example 4736-ethyl-5-(1-hydroxy-2-methylpropyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

473a)4′-{[4-ethyl-5-(1-hydroxy-2-methylpropyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(4-ethyl-5-formyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.6 g) and tetrahydrofuran (10 mL) was cooled to −78° C., isopropylGrignard reagent tetrahydrofuran solution (1.0 M, 1.9 mL) was addeddropwise, and the mixture was stirred for 1 hr. Then, the mixture wasgradually warmed to room temperature, and the mixture was stirred for 12hr. The solvent was evaporated from the reaction mixture under reducedpressure, and the residue was diluted with ethyl acetate. The dilutedsolution was washed with water and saturated brine, dried over anhydrousmagnesium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatographyto give the title compound as a colorless amorphous solid (0.38 g, 57%).

¹H NMR (300 MHz, CDCl₃) δ 0.76-1.15 (m, 8H), 1.27 (t, J=7.3, 3H),1.48-1.89 (m, 3H), 2.15-2.41 (m, 1H), 2.48-2.79 (m, 3H), 2.99-3.11 (m,1H), 4.27-4.44 (m, 1H), 4.80-5.10 (m, 1H), 5.35 (s, 2H), 7.23-7.38 (m,2H), 7.39-7.59 (m, 4H), 7.60-7.68 (m, 1H), 7.75 (d, J=7.7, 1H)

473b)6-ethyl-5-(1-hydroxy-2-methylpropyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.53 g), sodium hydrogencarbonate (0.75 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(1-hydroxy-2-methylpropyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.38 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.13 g, 29%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.73 (d, J=6.8, 3H), 0.86 (t, J=7.4, 3H),1.01 (d, J=6.8, 3H), 1.15 (t, J=7.4, 3H), 1.54-1.68 (m, 2H), 2.57-2.75(m, 4H), 3.55-3.66 (m, 1H), 4.51 (dd, J=8.8, 6.3, 1H), 5.02 (d, J=6.3,1H), 5.31 (s, 2H), 7.14-7.22 (m, 2H), 7.27-7.34 (m, 2H), 7.50-7.61 (m,2H), 7.63-7.73 (m, 2H), 12.39 (s, 1H)

473c)6-ethyl-5-(1-hydroxy-2-methylpropyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-ethyl-5-(1-hydroxy-2-methylpropyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.13 g) and ethanol (3 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (2.6 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.09 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.73 (d, J=6.8, 3H), 0.88 (t, J=7.4, 3H),0.99-1.07 (m, 3H), 1.15 (t, J=7.4, 3H), 1.58-1.73 (m, 2H), 2.58-2.74 (m,5H), 4.52 (dd, J=8.5, 6.0, 1H), 5.05 (d, J=6.0, 1H), 5.18-5.36 (m, 2H),7.03-7.09 (m, 2H), 7.25-7.32 (m, 3H), 7.32-7.45 (m, 2H), 7.47-7.52 (m,1H)

Example 4746-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-phenoxy-2-propylpyrimidin-4(3H)-one

474a)4′-[(4-methyl-6-oxo-5-phenoxy-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g), phenol (0.16 g), 8 M potassium hydroxide solution (0.2 mL) anddimethyl sulfoxide (5 mL) was stirred at 150° C. for 12 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.07 g, 13%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.4, 3H), 1.71-1.84 (m, 2H), 2.29(s, 3H), 2.65-2.74 (m, 2H), 5.35 (s, 2H), 6.90-7.05 (m, 3H), 7.24-7.33(m, 3H), 7.40-7.56 (m, 5H), 7.60-7.67 (m, 1H), 7.75 (dd, J=7.6, 0.9, 1H)

474b)6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-phenoxy-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.09 g), sodium hydrogencarbonate (0.13 g) and dimethyl sulfoxide (2 mL) was stirred at 40° C.for 30 min,4′-[(4-methyl-6-oxo-5-phenoxy-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.07 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-carbonyldiimidazole (0.04 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.03 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.01 g, 19%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.72-1.86 (m, 2H), 2.26(s, 3H), 2.66-2.74 (m, 2H), 5.26 (s, 2H), 6.84 (d, J=8.0, 2H), 7.00 (t,J=7.4, 1H), 7.18-7.31 (m, 6H), 7.38 (d, J=7.2, 1H), 7.47 (t, J=7.2, 1H),7.60 (t, J=7.0, 1H), 7.73-7.79 (m, 1H)

Example 4755-(4-tert-butoxyphenyl)-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methyl-2-propylpyrimidin-4(3H)-one

475a)4′-{[5-(4-tert-butoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-2′-fluorobiphenyl-2-carbonitrile(0.5 g), (4-tert-butoxyphenyl)boronic acid (0.26 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution(5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.51 g, 89%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.4, 3H), 1.37 (s, 9H), 1.73-1.88(m, 2H), 2.23 (s, 3H), 2.66-2.77 (m, 2H), 5.42 (s, 2H), 7.00-7.07 (m,2H), 7.20-7.35 (m, 5H), 7.43-7.51 (m, 2H), 7.61-7.69 (m, 1H), 7.74-7.80(m, 1H)

475b)5-(4-tert-butoxyphenyl)-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methyl-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.6 g), sodium hydrogencarbonate (0.85 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[5-(4-tert-butoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.51 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue wasdissolved in tetrahydrofuran (15 mL). N,N′-carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.44 g, 77%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.4, 3H), 1.33 (s, 9H), 1.60-1.75(m, 2H), 2.14 (s, 3H), 2.70 (t, J=7.4, 2H), 5.35 (s, 2H), 6.96-7.14 (m,4H), 7.17-7.29 (m, 3H), 7.53-7.64 (m, 2H), 7.67-7.75 (m, 2H), 12.48 (s,1H)

Example 4765-(4-methoxyphenoxy)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

476a)4′-{[5-(4-methoxyphenoxy)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.41 g), 4-methoxyphenol (0.13 g), 8 M potassium hydroxide solution(0.13 mL) and dimethyl sulfoxide (5 mL) was stirred at 150° C. for 12hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.12 g, 28%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.4, 3H), 1.70-1.83 (m, 2H), 2.30(s, 3H), 2.65-2.73 (m, 2H), 3.76 (s, 3H), 5.34 (s, 2H), 6.80-6.91 (m,4H), 7.27-7.33 (m, 2H), 7.41-7.50 (m, 2H), 7.50-7.55 (m, 2H), 7.60-7.68(m, 1H), 7.76 (dd, J=7.7, 0.9, 1H)

476b)5-(4-methoxyphenoxy)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogencarbonate (0.22 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C.for 30 min,4′-{[5-(4-methoxyphenoxy)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.12 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.06 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as colorlesscrystals (0.08 g, 56%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (t, J=7.4, 3H), 1.65-1.81 (m, 2H), 2.22(s, 3H), 2.60-2.69 (m, 2H), 3.74 (s, 3H), 5.16 (s, 2H), 6.63-6.78 (m,4H), 7.09-7.15 (m, 2H), 7.20-7.26 (m, 2H), 7.34-7.48 (m, 2H), 7.53-7.66(m, 2H)

476c)5-(4-methoxyphenoxy)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-(4-methoxyphenoxy)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.08 g) and ethanol (2 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (1.4 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.08 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.4, 3H), 1.59-1.75 (m, 2H), 2.17(s, 3H), 2.68 (t, J=7.4, 2H), 3.70 (s, 3H), 5.28 (s, 2H), 6.79-6.91 (m,4H), 7.08 (d, J=8.3, 2H), 7.30 (d, J=8.0, 3H), 7.33-7.47 (m, 2H), 7.51(dd, J=7.2, 1.5, 1H)

Example 477

5-(4-tert-butoxyphenyl)-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methyl-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-(4-tert-butoxyphenyl)-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methyl-2-propylpyrimidin-4(3H)-one(0.39 g) and ethanol (7 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (7 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.41 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.2, 3H), 1.33 (s, 9H), 1.63-1.79(m, 2H), 2.14 (s, 3H), 2.67-2.76 (m, 2H), 5.33 (s, 2H), 6.92-7.04 (m,3H), 7.09-7.26 (m, 4H), 7.33-7.52 (m, 3H), 7.58 (dd, J=7.4, 1.7, 1H)

Example 4785-(3,4-dimethoxyphenoxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

478a)4′-{[5-(3,4-dimethoxyphenoxy)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.8 g), 3,4-dimethoxyphenol (0.42 g), 8 M potassium hydroxide solution(0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.57 g, 61%).

¹H NMR (300 MHz, CDCl₃) δ 0.99 (t, J=7.4, 3H), 1.23 (t, J=7.4, 3H),1.73-1.87 (m, 2H), 2.60-2.75 (m, 4H), 3.80 (s, 3H), 3.84 (s, 3H), 5.36(s, 2H), 6.35 (dd, J=8.7, 2.8, 1H), 6.70 (d, J=2.8, 1H), 6.76 (d, J=8.9,1H), 7.29-7.36 (m, 2H), 7.36-7.48 (m, 2H), 7.50-7.55 (m, 2H), 7.56-7.65(m, 1H), 7.69-7.75 (m, 1H)

478b)5-(3,4-dimethoxyphenoxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogencarbonate (0.93 g) and dimethyl sulfoxide (15 mL) was stirred at 40° C.for 30 min,4′-{[5-(3,4-dimethoxyphenoxy)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.57 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.44 g, 77%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.13 (t, J=7.5, 3H),1.59-1.74 (m, 2H), 2.44-2.57 (m, 2H), 2.68 (t, J=7.3, 2H), 3.69 (s, 3H),3.72 (s, 3H), 5.33 (s, 2H), 6.26 (dd, J=8.9, 2.83, 1H), 6.65 (d, J=2.8,1H), 6.82 (d, J=8.9, 1H), 7.19-7.25 (m, 2H), 7.27-7.35 (m, 2H),7.49-7.61 (m, 2H), 7.64-7.74 (m, 2H), 12.40 (s, 1H)

Example 4796-ethyl-5-(3-methoxyphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

479a)4′-{[4-ethyl-5-(3-methoxyphenoxy)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.8 g), 3-methoxyphenol (0.34 g), 8 M potassium hydroxide solution(0.34 mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.45 g, 51%).

¹H NMR (300 MHz, CDCl₃) δ 0.99 (t, J=7.4, 3H), 1.22 (t, J=7.5, 3H),1.72-1.86 (m, 2H), 2.57-2.73 (m, 4H), 3.74 (s, 3H), 5.34 (s, 2H),6.48-6.60 (m, 3H), 7.13-7.21 (m, 1H), 7.32 (d, J=8.3, 2H), 7.36-7.47 (m,2H), 7.49-7.54 (m, 2H), 7.56-7.63 (m, 1H), 7.72 (dd, J=7.7, 0.9, 1H)

479b)6-ethyl-5-(3-methoxyphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.56 g), sodium hydrogencarbonate (0.79 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(3-methoxyphenoxy)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.45 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.23 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.27 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.12 (t, J=7.6, 3H),1.59-1.74 (m, 2H), 2.44-2.55 (m, 2H), 2.68 (t, J=7.4, 2H), 3.72 (s, 3H),5.33 (s, 2H), 6.39-6.52 (m, 2H), 6.60 (dd, J=8.2, 2.0, 1H), 7.14-7.27(m, 3H), 7.28-7.35 (m, 2H), 7.50-7.61 (m, 2H), 7.64-7.74 (m, 2H), 12.41(s, 1H)

Example 4806-ethyl-5-(4-ethylphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

480a)4′-{[4-ethyl-5-(4-ethylphenoxy)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.8 g), 4-ethylphenol (0.34 g), 8 M potassium hydroxide solution (0.34mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.59 g, 67%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.4, 3H), 1.14-1.26 (m, 6H),1.71-1.85 (m, 2H), 2.52-2.72 (m, 6H), 5.34 (s, 2H), 6.87 (d, J=8.7, 2H),7.10 (d, J=8.5, 2H), 7.28-7.46 (m, 4H), 7.48-7.61 (m, 3H), 7.69 (dd,J=7.7, 0.9, 1H)

480b)6-ethyl-5-(4-ethylphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.72 g), sodium hydrogencarbonate (1.03 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(4-ethylphenoxy)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.59 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.3 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.28 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.47 g, 71%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.07-1.20 (m, 6H),1.60-1.74 (m, 2H), 2.44-2.60 (m, 2H), 2.63-2.72 (m, 4H), 5.32 (s, 2H),6.76-6.83 (m, 2H), 7.13 (d, J=8.7, 2H), 7.20-7.26 (m, 2H), 7.30-7.36 (m,2H), 7.50-7.62 (m, 2H), 7.64-7.74 (m, 2H), 12.40 (s, 1H)

Example 4816-ethyl-5-(3-ethylphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

481a)4′-{[4-ethyl-5-(3-ethylphenoxy)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.8 g), 3-ethylphenol (0.34 g), 8 M potassium hydroxide solution (0.34mL) and dimethyl sulfoxide (10 mL) was stirred at 150° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.54 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 0.99 (t, J=7.4, 3H), 1.16-1.27 (m, 6H),1.73-1.86 (m, 2H), 2.56-2.73 (m, 6H), 5.34 (s, 2H), 6.73 (dd, J=7.9,2.1, 1H), 6.79-6.88 (m, 2H), 7.13-7.22 (m, 1H), 7.29-7.47 (m, 4H),7.49-7.54 (m, 2H), 7.55-7.63 (m, 1H), 7.68-7.74 (m, 1H)

481b)6-ethyl-5-(3-ethylphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogencarbonate (0.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(3-ethylphenoxy)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.47 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.4, 3H), 1.07-1.19 (m, 6H),1.59-1.76 (m, 2H), 2.44-2.62 (m, 4H), 2.65-2.72 (m, 2H), 5.33 (s, 2H),6.68 (dd, J=8.0, 2.2, 1H), 6.72-6.76 (m, 1H), 6.86 (d, J=7.5, 1H),7.16-7.26 (m, 3H), 7.28-7.34 (m, 2H), 7.49-7.60 (m, 2H), 7.64-7.75 (m,2H), 12.40 (s, 1H)

Example 4823-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(6-isopropoxypyridin-3-yl)-6-methyl-2-propylpyrimidin-4(3H)-one

482a)3′-fluoro-4′-{[5-(6-isopropoxypyridin-3-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.58 g), (6-isopropoxypyridin-3-yl)boronic acid (0.42 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution(5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.6 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.04 (t, J=7.4, 3H), 1.36 (d, J=6.2, 6H),1.74-1.89 (m, 2H), 2.29 (s, 3H), 2.68-2.79 (m, 2H), 5.26-5.38 (m, 1H),5.42 (s, 2H), 6.72-6.77 (m, 1H), 7.22-7.35 (m, 3H), 7.42-7.50 (m, 2H),7.58-7.68 (m, 2H), 7.76 (dd, J=8.1, 1.3, 1H), 8.10-8.13 (m, 1H)

482b)3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(6-isopropoxypyridin-3-yl)-6-methyl-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogencarbonate (1.01 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,3′-fluoro-4′-{[5-(6-isopropoxypyridin-3-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.6 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.29 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.49 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.4, 3H), 1.31 (d, J=6.2 6H),1.60-1.75 (m, 2H), 2.18 (s, 3H), 2.70 (t, J=7.4, 2H), 5.20-5.34 (m, 1H),5.36 (s, 2H), 6.76-6.81 (m, 1H), 7.03-7.13 (m, 2H), 7.22-7.30 (m, 1H),7.53-7.59 (m, 1H), 7.59-7.66 (m, 2H), 7.67-7.75 (m, 2H), 8.06-8.11 (m,1H), 12.49 (s, 1H)

Example 4836-ethyl-5-(6-isopropoxypyridin-3-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

483a)4′-{[4-ethyl-5-(6-isopropoxypyridin-3-yl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.6 g), (6-isopropoxypyridin-3-yl)boronic acid (0.43 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution(5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.57 g, 84%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.4, 3H), 1.22 (t, J=7.5, 3H), 1.36(d, J=6.0, 6H), 1.74-1.89 (m, 2H), 2.52 (q, J=7.5, 2H), 2.68-2.79 (m,2H), 5.28-5.43 (m, 3H), 6.75 (d, J=8.5, 1H), 7.33-7.50 (m, 4H),7.52-7.66 (m, 4H), 7.73 (dd, J=7.7, 1.1, 1H), 8.10 (d, J=2.1, 1H)

483b)6-ethyl-5-(6-isopropoxypyridin-3-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.68 g), sodium hydrogencarbonate (0.97 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-(6-isopropoxypyridin-3-yl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.57 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.28 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.48 g, 76%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.4, 3H), 1.12 (t, J=7.5, 3H),1.31 (d, J=6.2, 6H), 1.59-1.74 (m, 2H), 2.39 (q, J=7.5, 2H), 2.64-2.76(m, 2H), 5.20-5.39 (m, 3H), 6.79 (d, J=8.7, 1H), 7.24-7.36 (m, 4H),7.50-7.75 (m, 5H), 8.06 (d, J=2.1, 1H), 12.40 (s, 1H)

Example 4845-(2,5-difluorophenoxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

484a)4′-{[5-(2,5-difluorophenoxy)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g), 2,5-difluorophenol (0.23 g), 8 M potassium hydroxide solution(0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure and theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.29 g, 52%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.4, 3H), 1.24 (t, J=7.6, 3H),1.73-1.89 (m, 2H), 2.59-2.77 (m, 4H), 5.35 (s, 2H), 6.50-6.60 (m, 1H),6.61-6.70 (m, 1H), 7.01-7.14 (m, 1H), 7.26-7.34 (m, 2H), 7.39-7.50 (m,2H), 7.53 (d, J=8.3, 2H), 7.59-7.67 (m, 1H), 7.71-7.78 (m, 1H)

484b)5-(2,5-difluorophenoxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.35 g), sodium hydrogencarbonate (0.5 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[5-(2,5-difluorophenoxy)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.29 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.15 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.19 g, 57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.4, 3H), 1.16 (t, J=7.5, 3H),1.60-1.77 (m, 2H), 2.47-2.59 (m, 2H), 2.68 (t, J=7.5, 2H), 5.33 (s, 2H),6.81-6.93 (m, 2H), 7.19-7.43 (m, 5H), 7.46-7.61 (m, 2H), 7.64-7.74 (m,2H), 12.40 (s, 1H)

Example 4855-(1,3-benzodioxol-5-yloxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

485a)4′-{[5-(1,3-benzodioxol-5-yloxy)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.45 g), 1,3-benzodioxol-5-ol (0.21 g), 8 M potassium hydroxidesolution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C.for 12 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.44 g, 86%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.4, 3H), 1.22 (t, J=7.5, 3H),1.70-1.86 (m, 2H), 2.59-2.76 (m, 4H), 5.34 (s, 2H), 5.80 (s, 2H), 6.18(dd, J=8.3, 2.7, 1H), 6.34 (d, J=2.3, 1H), 6.52-6.57 (m, 1H), 6.62-6.68(m, 1H), 7.30 (s, 1H), 7.35-7.46 (m, 2H), 7.49-7.54 (m, 2H), 7.56-7.63(m, 1H), 7.71 (dd, J=7.7, 1.0, 1H)

485b)5-(1,3-benzodioxol-5-yloxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.52 g), sodium hydrogencarbonate (0.74 g) and dimethyl sulfoxide (8 mL) was stirred at 40° C.for 30 min,4′-{[5-(1,3-benzodioxol-5-yloxy)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.44 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.21 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.2 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.26 g, 53%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.12 (t, J=7.5, 3H),1.57-1.76 (m, 2H), 2.45-2.55 (m, 2H), 2.62-2.70 (m, 2H), 5.31 (s, 2H),5.98 (s, 2H), 6.29 (dd, J=8.5, 2.6, 1H), 6.64 (d, J=2.6, 1H), 6.76-6.81(m, 1H), 7.16-7.25 (m, 2H), 7.29-7.34 (m, 2H), 7.48-7.60 (m, 2H),7.63-7.74 (m, 2H), 12.40 (s, 1H)

Example 4865-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

486a)4′-{[5-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.45 g), 2,2-dimethyl-2,3-dihydro-1-benzofuran-7-ol (0.25 g), 8 Mpotassium hydroxide solution (0.19 mL) and dimethyl sulfoxide (8 mL) wasstirred at 150° C. for 12 hr. The reaction mixture was diluted withethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.21 g, 39%).

¹H NMR (300 MHz, CDCl₃) δ 0.98 (t, J=7.4, 3H), 1.22 (t, J=7.6, 3H), 1.51(s, 6H), 1.71-1.86 (m, 2H), 2.61-2.72 (m, 4H), 3.03 (s, 2H), 5.34 (s,2H), 6.55-6.61 (m, 1H), 6.65-6.73 (m, 1H), 6.81 (dd, J=7.3, 0.9, 1H),7.27-7.31 (m, 2H), 7.39-7.54 (m, 4H), 7.58-7.66 (m, 1H), 7.73 (dd,J=7.7, 0.9, 1H)

486b)5-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.24 g), sodium hydrogencarbonate (0.34 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[5-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.21 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.09 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL) were added, and themixture was stirred at room temperature for 2 hr. The reaction mixturewas diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.11 g, 49%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4, 3H), 1.11 (t, J=7.5, 3H),1.41 (s, 6H), 1.59-1.73 (m, 2H), 2.42-2.57 (m, 4H), 2.61-2.73 (m, 2H),5.32 (s, 2H), 6.50-6.56 (m, 1H), 6.63-6.70 (m, 1H), 6.81-6.87 (m, 1H),7.18-7.25 (m, 2H), 7.28-7.34 (m, 2H), 7.50-7.61 (m, 2H), 7.64-7.73 (m,2H), 12.40 (s, 1H)

Example 487

5-(3,4-dimethoxyphenoxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-(3,4-dimethoxyphenoxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.21 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.6 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.2 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.13 (t, J=7.5, 3H),1.62-1.76 (m, 2H), 2.45-2.56 (m, 2H), 2.70 (t, J=7.4, 2H), 3.69 (s, 3H),3.72 (s, 3H), 5.29 (s, 2H), 6.25 (dd, J=8.8, 2.9, 1H), 6.64 (d, J=2.8,1H), 6.84 (d, J=8.9, 1H), 7.12 (d, J=8.1, 2H), 7.27-7.36 (m, 3H),7.37-7.44 (m, 1H), 7.47 (dd, J=7.5, 1.7, 1H), 7.49-7.56 (m, 1H)

Example 488

6-ethyl-5-(3-methoxyphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-ethyl-5-(3-methoxyphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.7 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.2 g, 92%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.12 (t, J=7.5, 3H),1.63-1.78 (m, 2H), 2.43-2.56 (m, 2H), 2.66-2.77 (m, 2H), 3.72 (s, 3H),5.30 (s, 2H), 6.38-6.50 (m, 2H), 6.60 (dd, J=8.2, 2.0, 1H), 7.07-7.16(m, 2H), 7.16-7.24 (m, 1H), 7.27-7.34 (m, 3H), 7.34-7.48 (m, 2H), 7.53(dd, J=7.3, 1.4, 1H)

Example 489

6-ethyl-5-(4-ethylphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-ethyl-5-(4-ethylphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.7 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.17 g, 79%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.08-1.20 (m, 6H),1.62-1.77 (m, 2H), 2.44-2.60 (m, 4H), 2.65-2.75 (m, 2H), 5.29 (s, 2H),6.80 (d, J=8.7, 2H), 7.13 (dd, J=8.4, 2.9, 4H), 7.27-7.36 (m, 3H),7.37-7.44 (m, 1H), 7.44-7.51 (m, 1H), 7.55 (dd, J=7.4, 1.4, 1H)

Example 490

6-ethyl-5-(3-ethylphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-ethyl-5-(3-ethylphenoxy)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.21 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.18 g, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.08-1.19 (m, 6H),1.63-1.78 (m, 2H), 2.44-2.62 (m, 4H), 2.68-2.76 (m, 2H), 5.29 (s, 2H),6.67 (dd, J=7.9, 2.1, 1H), 6.71-6.76 (m, 1H), 6.83-6.89 (m, 1H),7.09-7.14 (m, 2H), 7.17-7.24 (m, 1H), 7.27-7.33 (m, 3H), 7.34-7.48 (m,2H), 7.53 (dd, J=7.4, 1.4, 1H)

Example 491

3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(6-isopropoxypyridin-3-yl)-6-methyl-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-(6-isopropoxypyridin-3-yl)-6-methyl-2-propylpyrimidin-4(3H)-one(0.21 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.2 g, 94%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.31 (d, J=6.2, 6H),1.61-1.76 (m, 2H), 2.17 (s, 3H), 2.67-2.76 (m, 2H), 5.21-5.37 (m, 3H),6.75-6.80 (m, 1H), 6.94-7.01 (m, 1H), 7.08-7.13 (m, 1H), 7.15-7.21 (m,1H), 7.37 (dd, J=7.5, 1.3, 1H), 7.40-7.53 (m, 2H), 7.55-7.60 (m, 1H),7.64 (dd, J=8.7, 2.5, 1H), 8.07-8.11 (m, 1H)

Example 492

6-ethyl-5-(6-isopropoxypyridin-3-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-ethyl-5-(6-isopropoxypyridin-3-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.19 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.12 (t, J=7.5, 3H),1.31 (d, J=6.2, 6H), 1.61-1.76 (m, 2H), 2.38 (q, J=7.5, 2H), 2.65-2.77(m, 2H), 5.19-5.38 (m, 3H), 6.78 (dd, J=8.6, 0.7, 1H), 7.15-7.21 (m,2H), 7.26-7.32 (m, 2H), 7.33-7.39 (m, 1H), 7.42 (dd, J=7.4, 1.5, 1H),7.47 (dd, J=7.5, 1.7, 1H), 7.51-7.57 (m, 1H), 7.63 (dd, J=8.7, 2.5, 1H),8.03-8.08 (m, 1H)

Example 493

5-(2,5-difluorophenoxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-(2,5-difluorophenoxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.14 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.19 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.15 (t, J=7.4, 3H),1.62-1.80 (m, 2H), 2.49-2.58 (m, 2H), 2.71 (t, J=7.4, 2H), 5.28 (s, 2H),6.83-6.92 (m, 2H), 7.12 (d, J=8.1, 2H), 7.26-7.33 (m, 3H), 7.32-7.47 (m,3H), 7.51 (dd, J=7.4, 1.4, 1H)

Example 494

5-(1,3-benzodioxol-5-yloxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-(1,3-benzodioxol-5-yloxy)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.2 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.12 (t, J=7.5, 3H),1.62-1.77 (m, 2H), 2.43-2.54 (m, 2H), 2.64-2.74 (m, 2H), 5.27 (s, 2H),5.98 (s, 2H), 6.28 (dd, J=8.5, 2.6, 1H), 6.63 (d, J=2.6, 1H), 6.80 (d,J=8.5, 1H), 7.09 (d, J=8.3, 2H), 7.24-7.32 (m, 3H), 7.33-7.47 (m, 2H),7.51 (dd, J=7.4, 1.4, 1H)

Example 495

5-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.07 g) and ethanol (2 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (2 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.08 g, 96%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.4, 3H), 1.11 (t, J=7.5, 3H),1.41 (s, 6H), 1.60-1.79 (m, 2H), 2.43-2.57 (m, 2H), 2.65-2.75 (m, 2H),3.02 (s, 2H), 5.27 (s, 2H), 6.49-6.53 (m, 1H), 6.64-6.71 (m, 1H),6.79-6.85 (m, 1H), 7.06-7.14 (m, 2H), 7.26-7.32 (m, 3H), 7.33-7.47 (m,2H), 7.51 (dd, J=7.4, 1.5, 1H)

Example 4965-[(4,6-dimethylpyridin-3-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

496a)4′-{[5-[(4,6-dimethylpyridin-3-yl)oxy]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.45 g), 4,6-dimethylpyridin-3-ol (0.19 g), 8 M potassium hydroxidesolution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C.for 12 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.4 g, 80%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.4, 3H), 1.18-1.28 (m, 5H),1.72-1.88 (m, 2H), 2.45 (s, 3H), 2.65 (s, 3H), 2.68-2.75 (m, 2H), 5.36(s, 2H), 6.74-6.81 (m, 1H), 6.86-6.92 (m, 1H), 7.31 (d, J=8.0, 2H),7.39-7.50 (m, 2H), 7.52-7.57 (m, 2H), 7.59-7.66 (m, 1H), 7.72-7.76 (m,1H)

496b)5-[(4,6-dimethylpyridin-3-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.49 g), sodium hydrogencarbonate (0.69 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,4′-{[5-[(4,6-dimethylpyridin-3-yl)oxy]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.4 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.2 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.19 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.27 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.13 (t, J=7.5, 3H),1.57-1.76 (m, 2H), 2.36 (s, 3H), 2.44-2.56 (m, 5H), 2.62-2.74 (m, 2H),5.32 (s, 2H), 6.84-6.90 (m, 1H), 6.92-6.98 (m, 1H), 7.19-7.26 (m, 2H),7.29-7.36 (m, 2H), 7.49-7.56, (m, 1H), 7.58 (dd, J=7.4, 1.1, 1H),7.64-7.74 (m, 2H), 12.42 (s, 1H)

Example 4975-[(4,6-dimethylpyridin-2-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

497a)4′-{[5-[(4,6-dimethylpyridin-2-yl)oxy]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.45 g), 4,6-dimethylpyridin-2-ol (0.19 g), 8 M potassium hydroxidesolution (0.19 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C.for 12 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.24 g, 48%).

¹H NMR (300 MHz, CDCl₃) δ 0.99 (t, J=7.4, 3H), 1.21 (t, J=7.6, 3H),1.63-1.89 (m, 2H), 2.27 (s, 3H), 2.33 (s, 3H), 2.52-2.73 (m, 4H), 5.36(s, 2H), 6.61 (s, 1H), 6.63 (s, 1H), 7.26-7.55 (m, 6H), 7.58-7.66 (m,1H), 7.74 (dd, J=7.8, 1.0, 1H)

497b)5-[(4,6-dimethylpyridin-2-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.29 g), sodium hydrogencarbonate (0.42 g) and dimethyl sulfoxide (6 mL) was stirred at 40° C.for 30 min,4′-{[5-[(4,6-dimethylpyridin-2-yl)oxy]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.24 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (8 mL). N,N′-carbonyldiimidazole (0.12 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.11 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.16 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.11 (t, J=7.5, 3H),1.57-1.73 (m, 2H), 2.24 (s, 3H), 2.28 (s, 3H), 2.41-2.53 (m, 2H),2.61-2.70 (m, 2H), 5.33 (s, 2H), 6.69 (s, 1H), 6.77 (s, 1H), 7.21-7.27(m, 2H), 7.27-7.33 (m, 2H), 7.51-7.61 (m, 2H), 7.64-7.74 (m, 2H), 12.39(s, 1H)

Example 498

5-[(4,6-dimethylpyridin-3-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidine-4(3H)potassium salt

To a mixture of5-[(4,6-dimethylpyridin-3-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.21 g, 99%).

¹H NMR (300 MHz, CDCl₃) δ 0.99 (t, J=7.4, 3H), 1.21 (t, J=7.6, 3H),1.63-1.89 (m, 2H), 2.27 (s, 3H), 2.33 (s, 3H), 2.52-2.73 (m, 4H), 5.36(s, 2H), 6.61 (s, 1H), 6.63 (s, 1H), 7.26-7.55 (m, 6H), 7.58-7.66 (m,1H), 7.74 (dd, J=7.8, 1.0, 1H)

Example 499

5-[(4,6-dimethylpyridin-2-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-[(4,6-dimethylpyridin-2-yl)oxy]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.13 g) and ethanol (3 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.13 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.11 (t, J=7.5, 3H),1.61-1.76 (m, 2H), 2.24 (s, 3H), 2.28 (s, 3H), 2.41-2.53 (m, 2H),2.62-2.74 (m, 2H), 5.29 (s, 2H), 6.68 (s, 1H), 6.77 (s, 1H), 7.09-7.15(m, 2H), 7.25-7.32 (m, 3H), 7.32-7.47 (m, 2H), 7.51 (dd, J=7.4, 1.5, 1H)

Example 5005-[6-(cyclopropylmethoxy)pyridin-3-yl]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

500a)4′-{[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g), [6-(cyclopropylmethoxy)pyridin-3-yl]boronic acid (0.38 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution(5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.5 g, 86%).

¹H NMR (300 MHz, CDCl₃) δ 0.31-0.40 (m, 2H), 0.55-0.66 (m, 2H), 1.01 (t,J=7.4, 3H), 1.17-1.38 (m, 4H), 1.73-1.90 (m, 2H), 2.51 (q, J=7.4, 2H),2.69-2.79 (m, 2H), 4.16 (d, J=7.2, 2H), 5.38 (s, 2H), 6.84 (d, J=7.9,1H), 7.33-7.51 (m, 4H), 7.52-7.57 (m, 2H), 7.58-7.66 (m, 2H), 7.74 (dd,J=7.7, 0.9, 1H), 8.08 (d, J=1.7, 1H)

500b)5-[6-(cyclopropylmethoxy)pyridin-3-yl]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.58 g), sodium hydrogencarbonate (0.83 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.5 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.32 g, 57%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.29-0.37 (m, 2H), 0.52-0.60 (m, 2H), 0.90(t, J=7.4, 3H), 1.08-1.35 (m, 4H), 1.59-1.74 (m, 2H), 2.38 (q, J=7.5,2H), 2.66-2.74 (m, 2H), 4.12 (d, J=7.2, 2H), 5.35 (s, 2H), 6.88 (d,J=8.5, 1H), 7.24-7.36 (m, 4H), 7.49-7.75 (m, 5H), 8.05 (d, J=1.9, 1H),12.41 (s, 1H)

Example 5015-[6-(cyclopropylmethoxy)pyridin-3-yl]-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methyl-2-propylpyrimidin-4(3H)-one

501a)4′-{[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.5 g), [6-(cyclopropylmethoxy)pyridin-3-yl]boronic acid (0.47 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution(5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.53 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 0.32-0.39 (m, 2H), 0.57-0.65 (m, 2H), 1.04 (t,J=7.4, 3H), 1.29-1.38 (m, 1H), 1.73-1.89 (m, 2H), 2.28 (s, 3H),2.68-2.78 (m, 2H), 4.16 (d, J=7.0, 2H), 5.42 (s, 2H), 6.81-6.87 (m, 1H),7.21-7.36 (m, 3H), 7.43-7.51 (m, 2H), 7.60-7.70 (m, 2H), 7.76 (dd,J=8.0, 1.2, 1H), 8.10 (d, J=1.7, 1H)

501b)5-[6-(cyclopropylmethoxy)pyridin-3-yl]-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methyl-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogencarbonate (1.01 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-[6-(cyclopropylmethoxy)pyridin-3-yl]-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.53 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.29 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.27 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.41 g, 60%).

¹H NMR (300 MHz, CDCl₃) δ 0.29-0.44 (m, 2H), 0.59-0.68 (m, 2H), 1.01 (t,J=7.4, 3H), 1.24-1.31 (m, 1H), 1.68-1.87 (m, 2H), 2.20 (s, 3H),2.63-2.78 (m, 2H), 4.09 (d, J=7.0, 2H), 5.26 (s, 2H), 6.63 (d, J=8.5,1H), 6.94-7.10 (m, 3H), 7.34-7.52 (m, 3H), 7.54-7.67 (m, 2H), 7.92 (d,J=2.1, 1H), 9.68 (s, 1H)

Example 5026-(1-morpholin-4-ylethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

502a)4′-{[4-(1-morpholin-4-ylethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) and morpholine (8 mL) was stirred at 90° C. for 12 hr. Thesolvent was evaporated from the reaction mixture under reduced pressure.The residue was diluted with ethyl acetate, washed with water andsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.43 g, 83%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (t, J=7.4, 3H), 1.35 (d, J=6.8, 3H),1.67-1.84 (m, 2H), 2.51-2.64 (m, 4H), 2.65-2.73 (m, 2H), 3.31 (q, J=6.8,1H), 3.69-3.78 (m, 4H), 5.29-5.48 (m, 2H), 6.53 (s, 1H), 7.32 (d, J=8.3,2H), 7.41-7.51 (m, 2H), 7.52-7.58 (m, 2H), 7.60-7.68 (m, 1H), 7.75 (dd,J=7.7, 0.9, 1H)

502b)6-(1-morpholin-4-ylethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.71 g), sodium hydrogencarbonate (1.01 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[4-(1-morpholin-4-ylethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.43 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.24 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.12 g, 26%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85 (t, J=7.4, 3H), 1.27 (d, J=6.8, 3H),1.55-1.69 (m, 2H), 2.45-2.54 (m, 4H), 2.61-2.70 (m, 2H), 3.34 (q, J=6.8,1H), 3.55-3.62 (m, 4H), 5.25-5.40 (m, 2H), 6.36 (s, 1H), 7.19-7.26 (m,2H), 7.29-7.35 (m, 2H), 7.49-7.61 (m, 2H), 7.64-7.74 (m, 2H), 12.36 (s,1H)

Example 5036-ethyl-5-[(4-methylpyridin-2-yl)oxy]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

503a)4′-{[4-ethyl-5-[(4-methylpyridin-2-yl)oxy]-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.45 g), 4-methylpyridin-2-ol (0.19 g), 8 M potassium hydroxidesolution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C.for 12 hr. The reaction mixture was diluted with ethyl acetate, washedwith water and then with saturated brine, and dried over anhydrousmagnesium sulfate. The solvent was evaporated under reduced pressure andthe residue was purified by silica gel column chromatography to give thetitle compound as a colorless amorphous solid (0.13 g, 25%).

¹H NMR (300 MHz, CDCl₃) δ 0.99 (t, J=7.4, 3H), 1.22 (t, J=8.3, 3H),1.72-1.86 (m, 2H), 2.34 (s, 3H), 2.57-2.72 (m, 4H), 5.33 (s, 2H), 6.79(d, J=5.3, 1H), 6.88 (s, 1H), 7.34 (d, J=8.3, 2H), 7.39-7.56 (m, 4H),7.59-7.66 (m, 1H), 7.74 (dd, J=7.7, 0.9, 1H), 7.97 (d, J=5.3, 1H)

503b)6-ethyl-5-[(4-methylpyridin-2-yl)oxy]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.17 g), sodium hydrogencarbonate (0.24 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min,4′-{[4-ethyl-5-[(4-methylpyridin-2-yl)oxy]-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.13 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.07 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.07 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.1 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.10 (t, J=7.6, 3H),1.58-1.73 (m, 2H), 2.33 (s, 3H), 2.46 (q, J=7.6, 2H), 2.62-2.72 (m, 2H),5.32 (s, 2H), 6.90-6.94 (m, 2H), 7.21-7.27 (m, 2H), 7.29-7.34 (m, 2H),7.51-7.61 (m, 2H), 7.64-7.74 (m, 2H), 7.92-7.97 (m, 1H), 12.39 (s, 1H)

503c)6-ethyl-5-[(4-methylpyridin-2-yl)oxy]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-ethyl-5-[(4-methylpyridin-2-yl)oxy]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.09 g) and ethanol (2 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (2 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.09 g, 97%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.10 (t, J=7.5, 3H),1.61-1.76 (m, 2H), 2.33 (s, 3H), 2.41-2.53 (m, 2H), 2.66-2.74 (m, 2H),5.28 (s, 2H), 6.88-6.96 (m, 2H), 7.11 (d, J=8.1, 2H), 7.25-7.48 (m, 5H),7.53 (dd, J=7.4, 1.3, 1H), 7.92-7.98 (m, 1H)

Example 504

5-[6-(cyclopropylmethoxy)pyridin-3-yl]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-[6-(cyclopropylmethoxy)pyridin-3-yl]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.21 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.22 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.29-0.37 (m, 2H), 0.52-0.59 (m, 2H), 0.93(t, J=7.4, 3H), 1.12 (t, J=7.5, 3H), 1.19-1.34 (m, 1H), 1.63-1.76 (m,2H), 2.37 (q, J=7.5, 2H), 2.67-2.77 (m, 2H), 4.12 (d, J=7.16, 2H), 5.30(s, 2H), 6.86 (d, J=8.5, 1H), 7.12-7.17 (m, J=8.1, 2H), 7.25-7.32 (m,3H), 7.33-7.46 (m, 2H), 7.48-7.52 (m, 1H), 7.65 (dd, J=8.5, 2.5, 1H),8.04 (d, J=1.9, 1H)

Example 505

5-[6-(cyclopropylmethoxy)pyridin-3-yl]-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methyl-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-[6-(cyclopropylmethoxy)pyridin-3-yl]-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-methyl-2-propylpyrimidin-4(3H)-one(0.21 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.21 g, 96%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.30-0.36 (m, 2H), 0.51-0.60 (m, 2H), 0.93(t, J=7.4, 3H), 1.18-1.32 (m, 1H), 1.61-1.77 (m, 2H), 2.16 (s, 3H),2.68-2.76 (m, 2H), 4.11 (d, J=7.2, 2H), 5.32 (s, 2H), 6.85 (d, J=8.5,1H), 6.91-6.99 (m, 1H), 7.06-7.20 (m, 2H), 7.33 (dd, J=7.4, 1.5, 1H),7.37-7.49 (m, 2H), 7.52-7.57 (m, 1H), 7.67 (dd, J=8.5, 2. 5, 1H), 8.07(d, J=1.9, 1H)

Example 506

6-(1-morpholin-4-ylethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-(1-morpholin-4-ylethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.08 g) and ethanol (2 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (2 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.08 g, 97%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (t, J=7.4, 3H), 1.26 (d, J=6.8, 3H),1.58-1.72 (m, 2H), 2.45-2.58 (m, 5H), 2.63-2.74 (m, 2H), 3.53-3.63 (m,4H), 5.20-5.32 (m, 2H), 6.34 (s, 1H), 7.04-7.14 (m, 2H), 7.26-7.32 (m,3H), 7.33-7.45 (m, 2H), 7.50 (dd, J=7.4, 1.5, 1H)

Example 5075-(6-ethoxypyridin-3-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

507a)4′-{[5-(6-ethoxypyridin-3-yl)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g), (6-ethoxypyridin-3-yl)boronic acid (0.23 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.05 g), 2 M aqueous cesium carbonate solution(5 mL) and 1,4-dioxane (5 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.54 g, 98%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (t, J=7.4, 3H), 1.21 (t, J=7.4, 3H), 1.40(t, J=7.2, 3H), 1.74-1.90 (m, 2H), 2.51 (q, J=7.4, 2H), 2.69-2.79 (m,2H), 4.39 (q, J=7.2, 2H), 5.37 (s, 2H), 6.79 (d, J=8.7, 1H), 7.36 (d,J=8.3, 2H), 7.39-7.51 (m, 2H), 7.51-7.58 (m, 2H), 7.58-7.68 (m, 2H),7.70-7.79 (m, 1H), 8.10 (d, J=1.9, 1H)

507b)5-(6-ethoxypyridin-3-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogencarbonate (0.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-(6-ethoxypyridin-3-yl)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.54 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.28 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.32 g, 60%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.12 (t, J=7.4, 3H),1.34 (t, J=7.1, 3H), 1.59-1.73 (m, 2H), 2.38 (q, J=7.4, 2H), 2.69 (t,J=7.3, 2H), 4.33 (q, J=7.1, 2H), 5.35 (s, 2H), 6.85 (d, J=8.5, 1H),7.23-7.34 (m, 4H), 7.50-7.75 (m, 5H), 8.06 (d, J=1.9, 1H)

Example 508

5-(6-ethoxypyridin-3-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-(6-ethoxypyridin-3-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.8 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.18 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.12 (t, J=7.4, 3H),1.34 (t, J=7.1, 3H), 1.61-1.75 (m, 2H), 2.38 (q, J=7.4, 2H), 2.71 (t,J=7.4, 2H), 4.33 (q, J=7.1, 2H), 5.31 (s, 2H), 6.84 (d, J=8.5, 1H),7.16-7.20 (m, 2H), 7.27-7.32 (m, 2H), 7.34-7.40 (m, 1H), 7.43 (dd,J=7.4, 1.5, 1H), 7.49 (dd, J=7.5, 1.7, 1H), 7.52-7.58 (m, 1H), 7.65 (dd,J=8.5, 2.5, 1H), 8.06 (d, J=1.9, 1H)

Example 5093-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-methyl-2-propylpyrimidin-4(3H)-one

509a)4′-{[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.6 g),[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]boronicacid (0.83 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution(6 mL) and 1,4-dioxane (6 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.76 g, 89%).

¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 6H), 0.84 (s, 9H), 0.95 (t, J=7.4,3H), 1.22 (s, 6H), 1.65-1.81 (m, 2H), 2.15 (s, 3H), 2.59-2.68 (m, 2H),3.51 (s, 2H), 5.34 (s, 2H), 6.94-7.02 (m, 2H), 7.11-7.26 (m, 5H),7.33-7.42 (m, 2H), 7.52-7.60 (m, 1H), 7.68 (dd, J=8.0, 1.2, 1H)

509b)3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-methyl-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.69 g), sodium hydrogencarbonate (0.99 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.76 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.29 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL), tetrabutylammonium fluoride tetrahydrofuransolution (1 mol/L, 2.3 mL) was added, and the mixture was stirred atroom temperature for 3 hr. The solvent was evaporated from the reactionmixture under reduced pressure. The residue was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.3 g, 68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (t, J=7.4, 3H), 1.04 (d, J=6.0, 3H),1.22 (s, 6H), 1.60-1.75 (m, 2H), 2.69 (t, J=7.5, 2H), 3.40 (d, J=5.6,2H), 4.85-4.99 (m, 1H), 5.35 (s, 2H), 6.99-7.14 (m, 4H), 7.16-7.28 (m,3H), 7.52-7.64 (m, 2H), 7.67-7.75 (m, 2H), 12.48 (s, 1H)

Example 5102-butyl-6-cyclopropyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

510a)4′-{[2-butyl-5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-2-butyl-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.6 g),[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]boronicacid (0.79 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution(6 mL) and 1,4-dioxane (6 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.69 g, 80%).

¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 6H), 0.70-0.78 (m, 2H), 0.79-0.87 (m,12H), 1.04-1.11 (m, 2H), 1.20-1.35 (m, 8H), 1.54-1.67 (m, 2H), 1.72-1.85(m, 1H), 2.59 (t, J=7.4, 2H), 3.51 (s, 2H), 5.27 (s, 2H), 6.95-7.04 (m,2H), 7.23-7.47 (m, 8H), 7.50-7.57 (m, 1H), 7.65 (dd, J=7.7, 0.9, 1H)

510b)2-butyl-6-cyclopropyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.62 g), sodium hydrogencarbonate (0.87 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[2-butyl-5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-cyclopropyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.69 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.25 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL), tetrabutylammonium fluoride tetrahydrofuransolution (1 mol/L, 1.5 mL) was added, and the mixture was stirred atroom temperature for 3 hr. The solvent was evaporated from the reactionmixture under reduced pressure. The residue was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.29 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.81-0.91 (m, 6H), 0.93-1.01 (m, 2H),1.24-1.41 (m, 8H), 1.52-1.66 (m, 2H), 1.73-1.85 (m, 1H), 2.63-2.75 (m,1H), 3.13-3.28 (m, 1H), 3.45 (s, 2H), 5.35 (s, 2H), 7.07-7.14 (m, 2H),7.23-7.40 (m, 6H), 7.49-7.62 (m, 2H), 7.66-7.74 (m, 2H), 12.04 (s, 1H)

Example 5116-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-propylpyrimidin-4(3H)-one

511a)4′-{[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]-3′-fluorobiphenyl-2-carbonitrile(0.6 g),[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]boronicacid (0.84 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution(6 mL) and 1,4-dioxane (6 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.78 g, 90%).

¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 6H), 0.84 (s, 9H), 0.95 (t, J=7.4,3H), 1.10 (t, J=7.5, 3H), 1.22 (s, 6H), 1.67-1.82 (m, 2H), 2.39 (q,J=7.5, 2H), 2.60-2.69 (m, 2H), 3.51 (s, 2H), 5.33 (s, 2H), 6.94-7.01 (m,2H), 7.10-7.24 (m, 5H), 7.33-7.41 (m, 2H), 7.52-7.60 (m, 1H), 7.65-7.70(m, 1H)

511b)6-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.66 g), sodium hydrogencarbonate (0.95 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}-3′-fluorobiphenyl-2-carbonitrile(0.74 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.27 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.25 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL), tetrabutylammonium fluoride tetrahydrofuransolution (1 mol/L, 2.4 mL) was added, and the mixture was stirred atroom temperature for 3 hr. The solvent was evaporated from the reactionmixture under reduced pressure. The residue was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.39 g, 82%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.11 (t, J=7.5, 3H),1.23 (s, 6H), 1.61-1.78 (m, 2H), 2.37 (q, J=7.5, 2H), 2.71 (t, J=7.4,2H), 3.22-3.46 (m, 4H), 5.34 (s, 2H), 6.99-7.20 (m, 6H), 7.22-7.30 (m,1H), 7.53-7.63 (m, 2H), 7.67-7.75 (m, 2H), 12.48 (s, 1H)

Example 5126-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

512a)4′-{[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.6 g),[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]boronicacid (0.84 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloromethane adduct (0.06 g), 2 M aqueous cesium carbonate solution(6 mL) and 1,4-dioxane (6 mL) was stirred at 100° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.99 g, 85%).

¹H NMR (300 MHz, CDCl₃) δ 0.00 (s, 6H), 0.84 (s, 9H), 0.92 (t, J=7.4,3H), 1.09 (t, J=7.5, 3H), 1.22 (s, 6H), 1.66-1.80 (m, 2H), 2.39 (q,J=7.5, 2H), 2.61-2.67 (m, 2H), 3.51 (s, 2H), 5.29 (s, 2H), 6.94-7.02 (m,2H), 7.11-7.17 (m, 2H), 7.22-7.41 (m, 4H), 7.42-7.47 (m, 2H), 7.50-7.56(m, 1H), 7.65 (dd, J=7.8, 0.9, 1H)

512b)6-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.92 g), sodium hydrogencarbonate (1.31 g) and dimethyl sulfoxide (12 mL) was stirred at 40° C.for 30 min,4′-{[5-[4-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethoxy)phenyl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.99 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (12 mL). N,N′-carbonyldiimidazole (0.38 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure. The residue was dissolved intetrahydrofuran (10 mL), tetrabutylammonium fluoride tetrahydrofuransolution (1 mol/L, 2.6 mL) was added, and the mixture was stirred atroom temperature for 3 hr. The solvent was evaporated from the reactionmixture under reduced pressure. The residue was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.38 g, 75%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.4, 3H), 1.11 (t, J=7.5, 3H),1.24 (s, 6H), 1.59-1.74 (m, 2H), 2.37 (q, J=7.4, 2H), 2.65-2.74 (m, 2H),3.42 (s, 2H), 5.35 (s, 2H), 7.05 (d, J=8.5, 2H), 7.19 (d, J=8.5, 2H),7.24-7.36 (m, 4H), 7.50-7.62 (m, 2H), 7.65-7.74 (m, 2H), 12.40 (s, 1H)

Example 513

3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-methyl-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-6-methyl-2-propylpyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.5 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.19 g, 87%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (t, J=7.4, 3H), 1.22 (s, 6H), 1.62-1.77(m, 2H), 2.13 (s, 3H), 2.71 (t, J=7.5, 2H), 3.37-3.49 (m, 3H), 5.32 (s,2H), 6.91-7.07 (m, 3H), 7.08-7.25 (m, 4H), 7.34-7.52 (m, 3H), 7.53-7.59(m, 1H)

Example 514

2-butyl-6-cyclopropyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-onepotassium salt

To a mixture of2-butyl-6-cyclopropyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.5 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.2 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84-0.91 (m, 6H), 0.93-0.99 (m, 2H),1.25-1.42 (m, 8H), 1.56-1.68 (m, 2H), 1.72-1.85 (m, 1H), 2.67-2.79 (m,2H), 3.15-3.25 (m, 1H), 3.37-3.47 (m, 1H), 5.32 (s, 2H), 7.10 (d,J=8.48, 2H), 7.17 (d, J=8.29, 2H), 7.30-7.50 (m, 7H), 7.56 (dd, J=7.35,1.51, 1H)

Example 515

6-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-2-propylpyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.5 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.18 g, 96%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (t, J=7.4, 3H), 1.12 (t, J=7.5, 3H),1.23 (s, 6H), 1.66-1.80 (m, 2H), 2.37 (q, J=7.5, 2H), 2.70-2.77 (m, 2H),3.38-3.49 (m, 3H), 5.32 (s, 2H), 6.93-7.07 (m, 3H), 7.09-7.21 (m, 4H),7.35-7.54 (m, 3H), 7.56-7.61 (m, 1H)

Example 516

6-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenyl]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.2 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.5 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.21 g, 93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.11 (t, J=7.5, 3H),1.23 (s, 6H), 1.62-1.76 (m, 2H), 2.36 (q, J=7.5, 2H), 2.67-2.75 (m, 2H),3.41 (s, 2H), 5.31 (s, 2H), 7.02-7.08 (m, 2H), 7.14-7.23 (m, 4H),7.28-7.32 (m, 2H), 7.34-7.40 (m, 1H), 7.43 (dd, J=7.44, 1.41, 1H),7.46-7.59 (m, 2H)

Example 5176-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenoxy]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

517a)4′-{[4-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenoxy]-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.52 g), 4-(2-hydroxy-1,1-dimethylethoxy)phenol (0.32 g), 8 M potassiumhydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirredat 150° C. for 12 hr. The reaction mixture was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.36 g, 58%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (t, J=7.4, 3H), 1.16-1.29 (m, 10H),1.73-1.86 (m, 2H), 2.39-2.50 (m, 1H), 2.62 (q, J=7.5, 2H), 2.67-2.74 (m,2H), 3.52-3.58 (m, 1H), 5.35 (s, 2H), 6.81-6.93 (m, 4H), 7.28-7.34 (m,2H), 7.40-7.50 (m, 2H), 7.52-7.56 (m, 2H), 7.60-7.67 (m, 1H), 7.73-7.78(m, 1H)

517b)6-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenoxy]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of4′-{[4-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenoxy]-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.36 g), tert-butyl(chloro)dimethylsilane (0.12 g), imidazole (0.14 g)and N,N′-dimethylformamide (10 mL) were stirred at room temperature for12 hr. The reaction mixture was diluted with ethyl acetate, washed withwater and then with saturated brine, and dried over anhydrous magnesiumsulfate. The solvent was evaporated under reduced pressure.

A mixture of hydroxylammonium chloride (0.34 g), sodium hydrogencarbonate (0.48 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min, the concentrate obtained above was added, and the mixturewas stirred at 90° C. for 12 hr. The reaction mixture was diluted withethyl acetate, washed with water and then with saturated brine, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure. The residue was dissolved in tetrahydrofuran (5 mL)N,N′-carbonyldiimidazole (0.14 g) and then1,8-diazabicyclo[5.4.0]undec-7-ene (0.13 mL) were added, and the mixturewas stirred at room temperature for 2 hr. The reaction mixture wasdiluted with ethyl acetate, washed with water and then with saturatedbrine, and dried over anhydrous magnesium sulfate. The solvent wasevaporated under reduced pressure. The residue was dissolved intetrahydrofuran (5 mL), tetrabutylammonium fluoride tetrahydrofuransolution (1 mol/L, 1.3 mL) was added, and the mixture was stirred atroom temperature for 3 hr. The solvent was evaporated from the reactionmixture under reduced pressure. The residue was diluted with ethylacetate, washed with water and then with saturated brine, and dried overanhydrous magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography to give the title compound as a colorless amorphous solid(0.15 g, 39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-1.02 (m, 6H), 1.11-1.25 (m, 8H),1.62-1.78 (m, 2H), 2.46-2.62 (m, 2H), 2.67-2.76 (m, 2H), 3.57-3.71 (m,1H), 5.37 (s, 2H), 6.80-6.87 (m, 2H), 6.94-7.00 (m, 2H), 7.23-7.30 (m,2H), 7.34-7.38 (m, 2H), 7.52-7.64 (m, 2H), 7.67-7.76 (m, 2H), 12.39 (s,1H)

Example 5185-[4-(2,2-dimethylpropoxy)phenyl]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

518a)4′-{[5-[4-(2,2-dimethylpropoxy)phenyl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of4′-{[4-ethyl-5-(4-hydroxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.52 g), 1-iodo-2,2-dimethylpropane (0.29 g), cesium carbonate (0.45 g)and dimethylformamide (10 mL) were stirred at 80° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure and the residue waspurified by silica gel column chromatography to give the title compoundas a colorless amorphous solid (0.37 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 0.98-1.07 (m, 12H), 1.18 (t, J=7.6, 3H),1.74-1.89 (m, 2H), 2.49 (q, J=7.6, 2H), 2.68-2.75 (m, 2H), 3.61 (s, 2H),5.37 (s, 2H), 6.93-7.00 (m, 2H), 7.20-7.27 (m, 2H), 7.34-7.56 (m, 6H),7.58-7.65 (m, 1H), 7.72-7.76 (m, 1H)

518b)5-[4-(2,2-dimethylpropoxy)phenyl]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of hydroxylammonium chloride (0.42 g), sodium hydrogencarbonate (0.6 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C.for 30 min,4′-{[5-[4-(2,2-dimethylpropoxy)phenyl]-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.37 g) was added, and the mixture was stirred at 90° C. for 12 hr. Thereaction mixture was diluted with ethyl acetate, washed with water andthen with saturated brine, and dried over anhydrous magnesium sulfate.The solvent was evaporated under reduced pressure. The residue wasdissolved in tetrahydrofuran (10 mL). N,N′-carbonyldiimidazole (0.17 g)and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added, andthe mixture was stirred at room temperature for 2 hr. The reactionmixture was diluted with ethyl acetate, washed with water and then withsaturated brine, and dried over anhydrous magnesium sulfate. The solventwas evaporated under reduced pressure and the residue was purified bysilica gel column chromatography to give the title compound as acolorless amorphous solid (0.2 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4, 3H), 1.02 (s, 9H), 1.10 (t,J=7.4, 3H), 1.52-1.73 (m, 2H), 2.36 (q, J=7.5, 2H), 2.64-2.72 (m, 2H),3.66 (s, 2H), 5.34 (s, 2H), 6.92-7.02 (m, 2H), 7.14-7.22 (m, 2H),7.22-7.28 (m, 2H), 7.30-7.35 (m, 2H), 7.50-7.60 (m, 2H), 7.64-7.73 (m,2H), 12.40 (s, 1H)

Example 519

6-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenoxy]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of6-ethyl-5-[4-(2-hydroxy-1,1-dimethylethoxy)phenoxy]-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.13 g) and ethanol (3 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (2.2 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.13 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.07-1.17 (m, 9H),1.59-1.78 (m, 2H), 2.65-2.75 (m, 2H), 3.27-3.39 (m, 4H), 4.83-4.95 (m,1H), 5.28 (s, 2H), 6.75-6.82 (m, 2H), 6.89-6.98 (m, 2H), 7.09 (d, J=8.3,2H), 7.25-7.33 (m, 3H), 7.33-7.46 (m, 2H), 7.51 (dd, J=7.4, 1.5, 1H)

Example 520

5-[4-(2,2-dimethylpropoxy)phenyl]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

To a mixture of5-[4-(2,2-dimethylpropoxy)phenyl]-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.19 g) and ethanol (4 mL) was added dropwise 0.1 M potassiumhydroxide-ethanol solution (3.3 mL), and the mixture was stirred at roomtemperature for 6 hr. The solvent was evaporated from the reactionmixture under reduced pressure to give crude crystals. The crudecrystals were recrystallized from hexane-diisopropyl ether (5:1) to givethe title compound as colorless crystals (0.2 g, 97%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.4, 3H), 1.02 (s, 9H), 1.10 (t,J=7.4, 3H), 1.62-1.78 (m, 2H), 2.36 (q, J=7.4, 2H), 2.66-2.75 (m, 2H),3.66 (s, 2H), 5.29 (s, 2H), 6.96 (d, J=8.7, 2H), 7.09-7.25 (m, 4H),7.27-7.33 (m, 3H), 7.33-7.47 (m, 2H), 7.49-7.53 (m, 1H)

Example 5216-ethyl-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

521a)4′-{[4-ethyl-5-(4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of (4-isopropoxyphenyl)boronic acid (0.31 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g) and4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.50 g, 89%).

¹H NMR (300 MHz, CDCl₃-d) δ 1.02 (3H, t, J=7.4 Hz), 1.18 (3H, t, J=7.4Hz), 1.35 (3H, d, J=6.0 Hz), 1.36 (3H, s), 1.74-1.89 (2H, m), 2.49 (2H,q, J=7.4 Hz), 2.68-2.77 (2H, m), 4.50-4.64 (1H, m), 5.37 (2H, s), 6.93(2H, d, J=8.67 Hz), 7.22 (2H, d, J=8.8 Hz), 7.36 (2H, d, J=8.4 Hz),7.41-7.56 (4H, m), 7.60-7.68 (1H, m), 7.76 (1H, dd, J=7.7, 0.94 Hz)

521b)6-ethyl-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

4′-{[4-Ethyl-5-(4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.5 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylaminehydrochloride (0.71 g) and sodium hydrogen carbonate (1 g) were added.The mixture was stirred overnight at 90° C. After cooling, the reactionmixture was diluted with ethyl acetate, washed with water, dried oversodium sulfate and concentrated. The residue was dissolved intetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.25 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.44 g, 79%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3 Hz), 1.10 (3H, t, J=7.4Hz), 1.29 (6H, d, J=6.0 Hz), 1.58-1.73 (2H, m), 2.37 (2H, q, J=7.4 Hz),2.68 (2H, t, J=7.4 Hz), 4.57-4.70 (1H, m), 5.34 (2H, s), 6.90-6.97 (2H,m), 7.14-7.21 (2H, m), 7.23-7.35 (4H, m), 7.49-7.61 (2H, m), 7.63-7.74(2H, m), 12.39 (1H, s)

521c)6-ethyl-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

6-Ethyl-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.07 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.32 g, 99%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.38 Hz), 1.10 (3H, t, J=7.57Hz), 1.28 (3H, s), 1.30 (3H, s), 1.61-1.77 (2H, m), 2.36 (2H, q, J=7.45Hz), 2.71 (2H, t, J=7.38 Hz), 4.57-4.71 (1H, m), 5.29 (2H, s), 6.93 (2H,d, J=8.71 Hz), 7.09-7.22 (4H, m), 7.26-7.46 (5H, m), 7.50 (1H, dd,J=7.57, 1.51 Hz)

Example 5222-butyl-5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-onepotassium salt

522a)4′-{[2-butyl-5-(4-isopropoxyphenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of (4-isopropoxyphenyl)boronic acid (0.31 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g) and4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.56 g, 99%).

¹H NMR (300 MHz, CDCl₃) δ 0.93 (3H, t, J=7.3 Hz), 1.32-1.49 (2H, m),1.35 (6H, d, J=6.0 Hz), 1.66-1.79 (2H, m), 2.24 (3H, s), 2.69-2.78 (2H,m), 4.50-4.65 (1H, m), 5.38 (2H, s), 6.89-6.97 (2H, m), 7.21-7.29 (2H,m), 7.35 (2H, d, J=8.4 Hz), 7.40-7.56 (4H, m), 7.60-7.68 (1H, m), 7.76(1H, dd, J=7.8, 0.85 Hz)

522b)2-butyl-5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one

4′-{[2-Butyl-5-(4-isopropoxyphenyl)-4-methyl-6-oxopyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.56 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylaminehydrochloride (0.79 g) and sodium hydrogen carbonate (1.2 g) were added.The mixture was stirred overnight at 90° C. After cooling, the reactionmixture was diluted with ethyl acetate, washed with water, dried oversodium sulfate and concentrated. The residue was dissolved intetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.28 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.49 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.82 (3H, t, J=7.5 Hz), 1.21-1.38 (8H, m),1.51-1.65 (2H, m), 2.13 (3H, s), 2.63-2.73 (2H, m), 4.56-4.72 (1H, m),5.35 (2H, s), 6.89-6.97 (2H, m), 7.16-7.36 (6H, m), 7.48-7.61 (2H, m),7.63-7.74 (2H, m), 12.40 (1H, s)

522c)2-butyl-5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-onepotassium salt

2-Butyl-5-(4-isopropoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}pyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.07 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.29 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.84 (3H, t, J=7.38 Hz), 1.21-1.42 (8H, m),1.54-1.69 (2H, m), 2.12 (3H, s), 2.70 (2H, t, J=7.57 Hz), 4.56-4.70 (1H,m), 5.30 (2H, s), 6.93 (2H, d, J=8.71 Hz), 7.12 (2H, d, J=7.95 Hz),7.18-7.46 (7H, m), 7.50 (1H, d, J=7.19 Hz)

Example 5235-[4-(cyclopropylmethoxy)phenyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

523a)4′-{[5-[4-(cyclopropylmethoxy)phenyl]-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of (bromomethyl)cyclopropane (0.17 mL), cesium carbonate (1.7g) and4′-{[5-(4-hydroxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.5 g) in N,N-dimethylformamide (5 mL) was stirred for 2 hr at 80° C.The reaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, dried over sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale yellow oil (0.56 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.31-0.40 (2H, m), 0.58-0.70 (2H, m), 1.02(3H, t, J=7.35 Hz), 1.21-1.38 (1H, m), 1.79 (2H, dd, J=15.45, 7.54 Hz),2.24 (3H, s), 2.67-2.75 (2H, m), 3.82 (2H, d, J=6.78 Hz), 5.37 (2H, s),6.91-6.99 (2H, m), 7.21-7.30 (2H, m), 7.35 (2H, d, J=8.48 Hz), 7.40-7.57(4H, m), 7.60-7.69 (1H, m), 7.76 (1H, dd, J=7.72, 0.75 Hz)

523b)5-[4-(cyclopropylmethoxy)phenyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

4′-{[5-[4-(Cyclopropylmethoxy)phenyl]-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.56 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylaminehydrochloride (0.79 g) and sodium hydrogen carbonate (1.2 g) were added.The mixture was stirred overnight at 90° C. After cooling, the reactionmixture was diluted with ethyl acetate, washed with water, dried oversodium sulfate and concentrated. The residue was dissolved intetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.28 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.49 g, 78%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.29-0.37 (2H, m), 0.53-0.63 (2H, m), 0.88(3H, t, J=7.44 Hz), 1.16-1.32 (1H, m), 1.54-1.71 (2H, m), 2.12 (3H, s),2.66 (2H, t, J=7.54 Hz), 3.84 (2H, d, J=6.97 Hz), 5.35 (2H, s),6.91-6.99 (2H, m), 7.18-7.35 (6H, m), 7.49-7.61 (2H, m), 7.64-7.74 (2H,m), 12.39 (1H, s)

Example 5245-(4-sec-butoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

524a)4′-{[5-(4-sec-butoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of 2-bromobutane (0.19 mL), cesium carbonate (1.7 g) and4′-{[5-(4-hydroxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.5 g) in N,N-dimethylformamide (5 mL) was stirred for 2 hr at 80° C.The mixture was diluted with ethyl acetate, washed with 1 M hydrochloricacid, dried over sodium sulfate and concentrated. The residue waspurified by silica gel column chromatography to give the title compoundas a pale yellow oil (0.5 g, 89%).

¹H NMR (300 MHz, CDCl₃) δ 0.94-1.06 (6H, m), 1.31 (3H, d, J=6.22 Hz),1.55-1.87 (4H, m), 2.25 (3H, s), 2.66-2.77 (2H, m), 4.24-4.39 (1H, m),5.38 (2H, s), 6.88-6.97 (2H, m), 7.21-7.28 (2H, m), 7.35 (2H, d, J=8.48Hz), 7.39-7.57 (4H, m), 7.59-7.68 (1H, m), 7.76 (1H, dd, J=7.82, 0.85Hz)

524b)5-(4-sec-butoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

4′-{[5-(4-sec-Butoxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.5 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylaminehydrochloride (0.79 g) and sodium hydrogen carbonate (1.2 g) were added.The mixture was stirred overnight at 90° C. After cooling, the reactionmixture was diluted with ethyl acetate, washed with water, dried oversodium sulfate and concentrated. The residue was dissolved intetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.28 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.45 g, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.83-0.99 (6H, m), 1.25 (3H, d, J=6.03 Hz),1.52-1.77 (4H, m), 2.13 (3H, s), 2.66 (2H, t, J=7.44 Hz), 4.34-4.49 (1H,m), 5.35 (2H, s), 6.89-6.98 (2H, m), 7.17-7.35 (6H, m), 7.49-7.61 (2H,m), 7.64-7.74 (2H, m), 12.39 (1H, s)

Example 525

5-(4-tert-Butoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-tert-Butoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.07 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.32 g, 100%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.35 Hz), 1.33 (9H, s),1.58-1.75 (2H, m), 2.12 (3H, s), 2.69 (2H, t, J=7.54 Hz), 5.30 (2H, s),6.95-7.03 (2H, m), 7.13 (2H, d, J=8.29 Hz), 7.20-7.46 (7H, m), 7.50 (1H,dd, J=7.35, 1.51 Hz)

Example 526

5-[4-(cyclopropylmethoxy)phenyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-[4-(Cyclopropylmethoxy)phenyl]-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.07 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.28 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.30-0.37 (2H, m), 0.53-0.62 (2H, m), 0.91(3H, t, J=7.35 Hz), 1.15-1.32 (1H, m), 1.58-1.74 (2H, m), 2.12 (3H, s),2.68 (2H, t, J=7.54 Hz), 3.84 (2H, d, J=6.97 Hz), 5.30 (2H, s), 6.94(2H, d, J=8.67 Hz), 7.12 (2H, d, J=8.29 Hz), 7.19-7.26 (2H, m),7.26-7.46 (5H, m), 7.50 (1H, dd, J=7.44, 1.41 Hz)

Example 527

5-(4-sec-butoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-sec-Butoxyphenyl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.07 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.29 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.87-0.99 (6H, m), 1.25 (3H, d, J=6.06 Hz),1.52-1.75 (4H, m), 2.13 (3H, s), 2.68 (2H, t, J=7.57 Hz), 4.34-4.47 (1H,m), 5.30 (2H, s), 6.93 (2H, d, J=8.71 Hz), 7.12 (2H, d, J=7.95 Hz), 7.22(2H, d, J=8.71 Hz), 7.29 (2H, d, J=8.33 Hz), 7.31-7.47 (3H, m),7.47-7.53 (1H, m)

Example 5285-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

528a)4′-{[5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid(0.33 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05g) and4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.58 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 1.02 (3H, t, J=7.35 Hz), 1.19 (3H, t, J=7.44Hz), 1.49 (6H, s), 1.74-1.90 (2H, m), 2.50 (2H, q, J=7.54 Hz), 2.68-2.77(2H, m), 3.04 (2H, s), 5.36 (2H, s), 6.76 (1H, d, J=8.29 Hz), 7.01 (1H,dd, J=8.10, 1.88 Hz), 7.10 (1H, d, J=1.32 Hz), 7.36 (2H, d, J=8.48 Hz),7.40-7.56 (4H, m), 7.60-7.68 (1H, m), 7.76 (1H, dd, J=7.63, 0.85 Hz)

528b)5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

4′-{[5-(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.58 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylaminehydrochloride (0.71 g) and sodium hydrogen carbonate (1 g) were added.The mixture was stirred overnight at 90° C. After cooling, the reactionmixture was diluted with ethyl acetate, washed with water, dried oversodium sulfate and concentrated. The residue was dissolved intetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.25 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.48 g, 74%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.38 Hz), 1.10 (3H, t, J=7.38Hz), 1.43 (6H, s), 1.59-1.73 (2H, m), 2.37 (2H, q, J=7.57 Hz), 2.68 (2H,t, J=7.19 Hz), 3.03 (2H, s), 5.33 (2H, s), 6.72 (1H, d, J=7.95 Hz), 6.95(1H, dd, J=8.14, 1.70 Hz), 7.07 (1H, s), 7.21-7.35 (4H, m), 7.50-7.60(2H, m), 7.64-7.73 (2H, m), 12.38 (1H, br. s.)

528c)5-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.07 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.21 g, 65%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.19 Hz), 1.10 (3H, t, J=7.38Hz), 1.43 (6H, s), 1.61-1.78 (2H, m), 2.37 (2H, q, J=7.45 Hz), 2.70 (2H,t, J=7.19 Hz), 3.03 (2H, s), 5.29 (2H, s), 6.71 (1H, d, J=8.33 Hz), 6.96(1H, d, J=8.33 Hz), 7.06-7.17 (3H, m), 7.25-7.46 (5H, m), 7.50 (1H, d,J=7.19 Hz)

Example 5295-(4-methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

529a)4′-{[5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of (4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronicacid (0.79 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(0.1 g) and4′-[(5-bromo-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (4 mL) was stirredovernight at 100° C. under an argon atmosphere. After cooling, thereaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.94 g, 76%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.44 Hz), 1.33 (3H, s), 1.45(3H, s), 1.64-1.94 (3H, m), 2.12-2.22 (1H, m), 2.25 (3H, s), 2.67-2.75(2H, m), 4.79-4.93 (1H, m), 5.36 (2H, s), 6.83 (1H, d, J=8.48 Hz), 7.13(1H, dd, J=8.29, 1.70 Hz), 7.33 (2H, d, J=8.10 Hz), 7.40-7.56 (5H, m),7.60-7.68 (1H, m), 7.72-7.79 (1H, m)

529b)4′-{[5-(4-methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of iodomethane (0.76 g), 60% sodium hydride (0.22 g) and4′-{[5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.56 g) in N,N-dimethylformamide (5 mL) was stirred for 1 hr. Thereaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was purified bysilica gel column chromatography to give the title compound as acolorless solid (0.38 g, 66%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.35 Hz), 1.34 (3H, s), 1.46(3H, s), 1.69-1.86 (2H, m), 1.91-2.02 (1H, m), 2.12 (1H, dd), 2.25 (3H,s), 2.65-2.77 (2H, m), 3.45 (3H, s), 4.49 (1H, dd, J=7.54, 6.03 Hz),5.38 (2H, s), 6.83 (1H, d, J=8.48 Hz), 7.14 (1H, dd, J=8.48, 2.07 Hz),7.34 (2H, d, J=8.10 Hz), 7.39-7.56 (5H, m), 7.59-7.69 (1H, m), 7.73-7.79(1H, m)

529c)5-(4-methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

4′-{[5-(4-Methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.38 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylaminehydrochloride (0.49 g) and sodium hydrogen carbonate (0.72 g) wereadded. The mixture was stirred overnight at 90° C. After cooling, thereaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was dissolved intetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.17 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.16 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.27 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.88 (3H, t, J=7.38 Hz), 1.31 (3H, s), 1.39(3H, s), 1.55-1.71 (2H, m), 1.88 (1H, dd, J=13.63, 7.19 Hz), 2.11-2.20(1H, m), 2.13 (3H, s), 2.66 (2H, t, J=7.38 Hz), 3.38 (3H, s), 4.43 (1H,t, J=6.25 Hz), 5.34 (2H, s), 6.76 (1H, d, J=8.33 Hz), 7.09 (1H, dd,J=8.33, 2.27 Hz), 7.22-7.35 (5H, m), 7.50-7.61 (2H, m), 7.64-7.73 (2H,m), 12.38 (1H, s)

529d)5-(4-methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-Methoxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.26 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.06 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.27 g, 97%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.38 Hz), 1.31 (3H, s), 1.39(3H, s), 1.57-1.75 (2H, m), 1.89 (1H, dd, J=13.63, 7.19 Hz), 2.09-2.20(4H, m), 2.68 (2H, t, J=7.57 Hz), 3.31 (3H, s), 4.43 (1H, t, J=6.25 Hz),5.30 (2H, s), 6.75 (1H, d, J=8.71 Hz), 7.05-7.15 (3H, m), 7.24-7.46 (6H,m), 7.47-7.54 (1H, m)

Example 5306-ethyl-5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

530a)4′-{[4-ethyl-5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of (4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)boronicacid (1.1 g), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(0.14 g) and4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(1.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (4 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the mixture was diluted with ethyl acetate, washed with water, driedover sodium sulfate and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a colorlesssolid (1.5 g, 82%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (3H, t, J=7.38 Hz), 1.19 (3H, t, J=7.57Hz), 1.33 (3H, s), 1.45 (3H, s), 1.73-1.94 (3H, m), 2.09-2.22 (1H, m),2.50 (2H, q, J=7.32 Hz), 2.67-2.77 (2H, m), 4.86 (1H, q, J=7.19 Hz),5.35 (2H, s), 6.83 (1H, d, J=8.33 Hz), 7.11 (1H, dd, J=8.52, 2.08 Hz),7.34 (2H, d, J=7.95 Hz), 7.39-7.56 (5H, m), 7.59-7.68 (1H, m), 7.76 (1H,d, J=7.57 Hz)

530b)6-ethyl-5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

To a mixture of4′-{[4-ethyl-5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(1.5 g) and 2,6-lutidine (0.98 mL) in dichloromethane (10 mL) was addedtriisopropylsilyl trifluoromethanesulfonate (1.5 mL) at 0° C. Afterstirring for 2 hr, the reaction mixture was diluted with ethyl acetate,washed with water, dried over sodium sulfate and concentrated. Theresidue was dissolved in dimethyl sulfoxide (5 mL), and thenhydroxylamine hydrochloride (1.7 g) and sodium hydrogen carbonate (2.5g) were added. The mixture was stirred overnight at 90° C. Aftercooling, the reaction mixture was diluted with ethyl acetate, washedwith water, dried over sodium sulfate and concentrated. The residue wasdissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.6g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.6 mL) were added. Afterstirring for 30 min, the reaction mixture was diluted with ethylacetate, washed with 1 M hydrochloric acid, dried over sodium sulfateand concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (1.3 g,77%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.19 Hz), 1.11 (3H, t, J=7.38Hz), 1.27 (3H, s), 1.39 (3H, s), 1.58-1.81 (3H, m), 2.09 (1H, dd,J=13.25, 6.06 Hz), 2.38 (2H, q, J=7.57 Hz), 2.68 (2H, t, J=7.38 Hz),4.63-4.76 (1H, m), 5.30-5.38 (2H, m), 6.72 (1H, d, J=8.71 Hz), 7.01 (1H,dd, J=8.33, 2.27 Hz), 7.21-7.37 (5H, m), 7.49-7.61 (2H, m), 7.63-7.74(2H, m), 12.38 (1H, s)

Example 531

5-(2,2-dimethyl-4-oxo-3,4-dihydro-2H-chromen-6-yl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of6-ethyl-5-(4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-6-yl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.78 g) and 1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3(1H)-one(0.84 g) in dichloromethane (8 mL) was stirred for 1 hr. The reactionmixture was diluted with ethyl acetate, washed with water, dried oversodium sulfate and concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound as a colorless solid(0.63 g, 81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.19 Hz), 1.11 (3H, t, J=7.57Hz), 1.43 (6H, s), 1.59-1.74 (2H, m), 2.37 (2H, q, J=7.32 Hz), 2.69 (2H,t, J=7.19 Hz), 2.83 (2H, s), 5.34 (2H, s), 7.03 (1H, d, J=8.33 Hz),7.22-7.35 (4H, m), 7.44-7.74 (6H, m), 12.38 (1H, s)

Example 532

5-(4-ethoxyphenyl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of (4-ethoxyphenyl)boronic acid (0.29 g),[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (0.05 g) and4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was dissolved indimethyl sulfoxide (5 mL), and then hydroxylamine hydrochloride (0.8 g)and sodium hydrogen carbonate (1.2 g) were added. The mixture wasstirred overnight at 90° C. After cooling, the reaction mixture wasdiluted with ethyl acetate, washed with water, dried over sodium sulfateand concentrated. The residue was dissolved in tetrahydrofuran (5 mL),and N,N′-carbonyldiimidazole (0.28 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added. After stirringfor 30 min, the mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, dried over sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.41 g, 66%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3 Hz), 1.10 (3H, t, J=7.5Hz), 1.35 (3H, t, J=7.0 Hz), 1.59-1.73 (2H, m), 2.36 (2H, q, J=7.5 Hz),2.68 (2H, t, J=7.3 Hz), 4.05 (2H, q, J=7.0 Hz), 5.34 (2H, s), 6.91-6.99(2H, m), 7.15-7.35 (6H, m), 7.49-7.74 (4H, m), 12.39 (1H, br. s.)

Example 533

5-(4-tert-butoxyphenyl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of (4-tert-butoxyphenyl)boronic acid (0.33 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.05 g) and4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was dissolved indimethyl sulfoxide (5 mL), and then hydroxylamine hydrochloride (0.8 g)and sodium hydrogen carbonate (1.2 g) were added. The mixture wasstirred overnight at 90° C. After cooling, the reaction mixture wasdiluted with ethyl acetate, washed with water, dried over sodium sulfateand concentrated. The residue was dissolved in tetrahydrofuran (5 mL),and N,N′-carbonyldiimidazole (0.28 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.46 g, 72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3 Hz), 1.10 (3H, t, J=7.4Hz), 1.33 (9H, s), 1.59-1.73 (2H, m), 2.36 (2H, q, J=7.5 Hz), 2.69 (2H,t, J=7.3 Hz), 5.34 (2H, s), 7.00 (2H, d, J=8.7 Hz), 7.19 (2H, d, J=8.5Hz), 7.24-7.35 (4H, m), 7.55 (2H, dd, J=15.7, 7.6 Hz), 7.64-7.74 (2H,m), 12.39 (1H, br. s.)

Example 534

5-(4-ethoxyphenyl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-Ethoxyphenyl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.07 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.31 g, 95%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.3 Hz), 1.10 (3H, t, J=7.5Hz), 1.35 (3H, t, J=7.0 Hz), 1.62-1.78 (2H, m), 2.36 (2H, q, J=7.5 Hz),2.71 (2H, t, J=7.3 Hz), 4.05 (2H, q, J=7.0 Hz), 5.29 (2H, s), 6.91-6.99(2H, m), 7.09-7.23 (4H, m), 7.25-7.53 (6H, m)

Example 535

5-(4-tert-butoxyphenyl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-tert-Butoxyphenyl)-6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.31 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.07 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.31 g, 91%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.3 Hz), 1.10 (3H, t, J=7.4Hz), 1.33 (9H, s), 1.62-1.77 (2H, m), 2.36 (2H, q, J=7.4 Hz), 2.72 (2H,t, J=7.3 Hz), 5.29 (2H, s), 6.97-7.03 (2H, m), 7.10-7.23 (4H, m),7.26-7.52 (6H, m)

Example 536

5-(4-tert-butoxyphenyl)-6-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of (4-tert-butoxyphenyl)boronic acid (0.33 g),[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (0.05 g) and3′-fluoro-4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile(0.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was dissolved indimethyl sulfoxide (5 mL), and then hydroxylamine hydrochloride (0.8 g)and sodium hydrogen carbonate (1.2 g) were added. The mixture wasstirred overnight at 90° C. After cooling, the reaction mixture wasdiluted with ethyl acetate, washed with water, dried over sodium sulfateand concentrated. The residue was dissolved in tetrahydrofuran (5 mL),and N,N′-carbonyldiimidazole (0.28 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.26 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.5 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.2 Hz), 1.11 (3H, t, J=7.4Hz), 1.33 (9H, s), 1.63-1.77 (2H, m), 2.37 (2H, q, J=7.6 Hz), 2.71 (2H,t, J=7.2 Hz), 5.34 (2H, s), 6.96-7.28 (7H, m), 7.52-7.75 (4H, m), 12.47(1H, s)

Example 537

5-(4-tert-butoxyphenyl)-6-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-tert-Butoxyphenyl)-6-ethyl-3-{[3-fluoro-2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.31 g) was dissolved in ethanol (3 mL), and 8 M potassium hydroxidesolution (0.07 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.31 g, 91%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.4 Hz), 1.11 (3H, t, J=7.6Hz), 1.33 (9H, s), 1.65-1.80 (2H, m), 2.37 (2H, q, J=7.6 Hz), 2.73 (2H,t, J=7.4 Hz), 5.30 (2H, s), 6.88-7.03 (3H, m), 7.08-7.21 (4H, m),7.29-7.48 (3H, m), 7.50-7.57 (1H, m)

Example 538

6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one

A mixture of 1,1,1-trifluoro-2-iodoethane (0.91 mL), cesium carbonate(1.5 g) and4′-{[5-(4-hydroxyphenyl)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(1 g) in N,N-dimethylformamide (10 mL) was stirred overnight at 100° C.The reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate and concentrated. The residue was dissolved indimethyl sulfoxide (6 mL), and hydroxylamine hydrochloride (0.79 g) andsodium hydrogen carbonate (1.2 g) were added. The mixture was stirredovernight at 90° C. After cooling, the reaction mixture was diluted withethyl acetate, washed with water, dried over sodium sulfate andconcentrated. The residue was dissolved in tetrahydrofuran (5 mL), andN,N′-carbonyldiimidazole (0.28 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene(0.26 mL) were added. After stirring for 30 min, the reaction mixturewas diluted with ethyl acetate, washed with 1 M hydrochloric acid, driedover sodium sulfate and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale yellowsolid (0.41 g, 62%).

¹H NMR (300 MHz, DMSO-d₆) 6.0.88 (3H, t, J=7.3 Hz), 1.55-1.72 (2H, m),2.12 (3H, s), 2.66 (2H, t, J=7.5 Hz), 4.80 (2H, q, J=8.9 Hz), 5.35 (2H,s), 7.05-7.14 (2H, m), 7.23-7.36 (6H, m), 7.48-7.75 (4H, m), 12.40 (1H,br. s.)

Example 539

6-methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-onepotassium salt

6-Methyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (10 mL), and 8 M potassium hydroxidesolution (0.065 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.32 g, 97%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.3 Hz), 1.58-1.76 (2H, m),2.12 (3H, s), 2.69 (2H, t, J=7.4 Hz), 4.80 (2H, q, J=9.0 Hz), 5.31 (2H,s), 7.05-7.16 (4H, m), 7.24-7.54 (8H, m)

Example 5406-(1-fluoroethyl)-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

540a) 6-(1-fluoroethyl)-2-propylpyrimidin-4(3H)-one

A mixture of ethyl 4-fluoro-3-oxopentanoate (5.0 g), butanimidamidehydrochloride (4.6 g) and sodium methoxide (28% methanol solution, 16mL) in methanol (50 mL) was stirred overnight. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid, driedover sodium sulfate and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale yellowoil (5.7 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.3 Hz), 1.55-1.68 (3H, m),1.74-1.90 (2H, m), 2.63-2.70 (2H, m), 5.23-5.49 (1H, m), 6.48 (1H, s),13.17 (1H, br. s.)

540b)4′-{[4-(1-fluoroethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of 6-(1-fluoroethyl)-2-propylpyrimidin-4(3H)-one (5.7 g),4′-(bromomethyl)biphenyl-2-carbonitrile (9.3 g) and potassium carbonate(8.5 g) in acetonitrile (50 mL) was stirred overnight at 50° C. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, dried over sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale yellow solid (5 g, 43%).

¹H NMR (300 MHz, CDCl₃) δ 0.96 (3H, t, J=7.3 Hz), 1.56-1.83 (5H, m),2.63-2.71 (2H, m), 5.21-5.51 (3H, m), 6.57 (1H, s), 7.30 (2H, d, J=8.3Hz), 7.41-7.81 (6H, m)

540c)4′-{[5-bromo-4-(1-fluoroethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of sodium acetate (1.2 g) and4′-{[4-(1-fluoroethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(5 g) in acetic acid (50 mL) was added bromine (0.72 mL), and themixture was stirred for 4 hr. Acetic acid was removed in vacuo, and themixture was diluted with ethyl acetate, washed with saturated aqueoussodium hydrogen carbonate, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a pale yellow solid (5 g, 83%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.3 Hz), 1.51-1.78 (5H, m),2.71-2.79 (2H, m), 5.42 (2H, s), 5.75-6.02 (1H, m), 7.34 (2H, d, J=8.3Hz), 7.55-7.65 (4H, m), 7.76-7.83 (1H, m), 7.95 (1H, dd, J=7.8, 0.8 Hz)

540d)6-(1-fluoroethyl)-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of (4-isopropoxyphenyl)boronic acid (0.27 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.041 g) and4′-{[5-bromo-4-(1-fluoroethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.45 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate, passed through silica gel pad andconcentrated. The residue was dissolved in dimethyl sulfoxide (5 mL),and hydroxylamine hydrochloride (0.7 g) and sodium hydrogen carbonate (1g) were added. The mixture was stirred overnight at 90° C. Aftercooling, the reaction mixture was diluted with ethyl acetate, washedwith water, dried over sodium sulfate and concentrated. The residue wasdissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.24g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added. Afterstirring for 30 min, the reaction mixture was diluted with ethylacetate, washed with 1 M hydrochloric acid, dried over sodium sulfateand concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.22 g,39%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.4 Hz), 1.29 (6H, d, J=6.1Hz), 1.47-1.78 (5H, m), 2.73 (2H, t, J=7.2 Hz), 4.60-4.71 (1H, m),5.21-5.44 (3H, m), 6.97 (2H, d, J=8.7 Hz), 7.18-7.36 (6H, m), 7.50-7.61(2H, m), 7.64-7.73 (2H, m), 12.39 (1H, s)

Example 541

5-(4-tert-butoxyphenyl)-6-(1-fluoroethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of (4-tert-butoxyphenyl)boronic acid (0.29 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.041 g) and4′-{[5-bromo-4-(1-fluoroethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.45 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the mixture was diluted with ethyl acetate, washed with water, driedover sodium sulfate, passed through silica gel pad and concentrated. Theresidue was dissolved in dimethyl sulfoxide (5 mL), and hydroxylaminehydrochloride (0.7 g) and sodium hydrogen carbonate (1 g) were added.The mixture was stirred overnight at 90° C. After cooling, the reactionmixture was diluted with ethyl acetate, washed with water, dried oversodium sulfate and concentrated. The residue was dissolved intetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.24 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.30 g, 52%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.91 (3H, t, J=7.4 Hz), 1.34 (9H, s),1.49-1.76 (5H, m), 2.74 (2H, t, J=7.2 Hz), 5.19-5.45 (3H, m), 7.04 (2H,d, J=8.3 Hz), 7.22 (2H, d, J=8.3 Hz), 7.26-7.36 (4H, m), 7.50-7.61 (2H,m), 7.64-7.74 (2H, m), 12.39 (1H, s)

Example 5426-(difluoromethyl)-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

542a) 6-(difluoromethyl)-2-propylpyrimidin-4(3H)-one

A mixture of ethyl 4,4-difluoro-3-oxobutanoate (5.0 g), butanimidamidehydrochloride (4.1 g) and sodium methoxide (28% methanol solution, 15mL) in methanol (50 mL) was stirred overnight. The reaction mixture wasdiluted with ethyl acetate, washed with 1 M hydrochloric acid, driedover sodium sulfate and concentrated. The residue was purified by silicagel column chromatography to give the title compound as a pale yellowoil (5.6 g, 100%).

¹H NMR (300 MHz, CDCl₃) δ 0.98 (3H, t, J=7.3 Hz), 1.71-1.86 (2H, m),2.61-2.68 (2H, m), 6.13-6.57 (2H, m)

542b)4′-{[4-(difluoromethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of 6-(difluoromethyl)-2-propylpyrimidin-4(3H)-one (5.6 g),4′-(bromomethyl)biphenyl-2-carbonitrile (9 g) and potassium carbonate(8.3 g) in acetonitrile (60 mL) was stirred overnight at 50° C. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, dried over sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale yellow solid (4.4 g, 38%).

¹H NMR (300 MHz, CDCl₃) δ 0.98 (3H, t, J=7.4 Hz), 1.71-1.85 (2H, m),2.67-2.77 (2H, m), 5.38 (2H, s), 6.14-6.77 (2H, m), 7.23-7.33 (2H, m),7.40-7.81 (6H, m)

542c)4′-{[5-bromo-4-(difluoromethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of sodium acetate (1 g) and4′-{[4-(difluoromethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(4.4 g) in acetic acid (44 mL) was added bromine (0.62 mL), and themixture was stirred for 4 hr. Acetic acid was removed in vacuo, and themixture was diluted with ethyl acetate, washed with saturated aqueoussodium hydrogen carbonate, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a pale yellow solid (2.7 g, 61%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.4 Hz), 1.74-1.89 (2H, m),2.69-2.81 (2H, m), 5.42 (2H, s), 6.81 (1H, t, J=53.8 Hz), 7.32 (2H, d,J=8.3 Hz), 7.40-7.81 (6H, m)

542d)6-(difluoromethyl)-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of (4-isopropoxyphenyl)boronic acid (0.27 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.041 g) and4′-{[5-bromo-4-(difluoromethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.46 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate, passed through silica gel pad andconcentrated. The residue was dissolved in dimethyl sulfoxide (5 mL),and hydroxylamine hydrochloride (0.7 g) and sodium hydrogen carbonate (1g) were added. The mixture was stirred overnight at 90° C. Aftercooling, the reaction mixture was diluted with ethyl acetate, washedwith water, dried over sodium sulfate and concentrated. The residue wasdissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.24g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added. Afterstirring for 30 min, the reaction mixture was diluted with ethylacetate, washed with 1 M hydrochloric acid, dried over sodium sulfateand concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.41 g,72%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.4 Hz), 1.30 (6H, d, J=6.0Hz), 1.58-1.74 (2H, m), 2.75 (2H, t, J=7.3 Hz), 4.59-4.75 (1H, m), 5.39(2H, s), 6.47 (1H, t, J=53.4 Hz), 6.96-7.03 (2H, m), 7.20-7.37 (6H, m),7.50-7.74 (4H, m), 12.40 (1H, br. s.)

Example 543

5-(4-tert-butoxyphenyl)-6-(difluoromethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of (4-tert-butoxyphenyl)boronic acid (0.29 g),[1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium (0.041 g) and4′-{[5-bromo-4-(difluoromethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.45 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate, passed through silica gel pad andconcentrated. The residue was dissolved in dimethyl sulfoxide (5 mL),and hydroxylamine hydrochloride (0.7 g) and sodium hydrogen carbonate (1g) were added. The mixture was stirred overnight at 90° C. Aftercooling, the reaction mixture was diluted with ethyl acetate, washedwith water, dried over sodium sulfate and concentrated. The residue wasdissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.24g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added. Afterstirring for 30 min, the reaction mixture was diluted with ethylacetate, washed with 1 M hydrochloric acid, dried over sodium sulfateand concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.4 g,68%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (3H, t, J=7.4 Hz), 1.35 (9H, s),1.59-1.74 (2H, m), 2.76 (2H, t, J=7.4 Hz), 5.39 (2H, s), 6.46 (1H, t,J=53.4 Hz), 7.06 (2H, d, J=8.7 Hz), 7.21-7.36 (6H, m), 7.48-7.75 (4H,m), 12.40 (1H, s)

Example 544

6-(1-fluoroethyl)-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

6-(1-Fluoroethyl)-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.2 g) was dissolved in ethanol (5 mL), and 8 M potassium hydroxidesolution (0.044 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.18 g, 84%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.4 Hz), 1.29 (6H, d, J=6.1Hz), 1.47-1.81 (5H, m), 2.65-2.88 (2H, m), 4.58-4.74 (1H, m), 5.18-5.47(3H, m), 6.96 (2H, d, J=8.7 Hz), 7.12-7.26 (4H, m), 7.26-7.54 (6H, m)

Example 545

5-(4-tert-butoxyphenyl)-6-(1-fluoroethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-tert-Butoxyphenyl)-6-(1-fluoroethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.21 g) was dissolved in ethanol (5 mL), and 8 M potassium hydroxidesolution (0.044 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.18 g, 82%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.94 (3H, t, J=7.2 Hz), 1.34 (9H, s),1.47-1.80 (5H, m), 2.68-2.87 (2H, m), 5.17-5.44 (3H, m), 7.03 (2H, d,J=8.7 Hz), 7.12-7.55 (10H, m)

Example 546

6-(difluoromethyl)-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

6-(Difluoromethyl)-5-(4-isopropoxyphenyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (5 mL), and 8 M potassium hydroxidesolution (0.066 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.29 g, 89%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.4 Hz), 1.30 (6H, d, J=6.1Hz), 1.61-1.77 (2H, m), 2.78 (2H, t, J=7.4 Hz), 4.59-4.74 (1H, m), 5.34(2H, s), 6.45 (1H, t, J=53.6 Hz), 6.99 (2H, d, J=8.7 Hz), 7.12-7.55(10H, m)

Example 547

5-(4-tert-butoxyphenyl)-6-(difluoromethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-tert-Butoxyphenyl)-6-(difluoromethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.31 g) was dissolved in ethanol (5 mL), and 8 M potassium hydroxidesolution (0.066 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.28 g, 85%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.93 (3H, t, J=7.4 Hz), 1.35 (9H, s),1.62-1.77 (2H, m), 2.79 (2H, t, J=7.4 Hz), 5.34 (2H, s), 6.45 (1H, t,J=53.4 Hz), 7.01-7.54 (12H, m)

Example 548

6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]pyrimidin-4(3H)-one

To a solution of tetrahydro-2H-pyran-4-ol (0.23 mL), triphenylphosphine(1.2 g) and4′-{[4-ethyl-5-(4-hydroxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(1 g) in tetrahydrofuran (5 mL) was added diisopropyl azodicarboxylate(2.3 mL, 1.9 M toluene solution), and the mixture was stirred for 2 hrat 50° C. After cooling, the reaction mixture was diluted with ethylacetate, washed with water, dried over sodium sulfate and concentrated.The residue was dissolved in dimethyl sulfoxide (5 mL), andhydroxylamine hydrochloride (0.72 g) and sodium hydrogen carbonate (1 g)were added. The mixture was stirred overnight at 90° C. After cooling,the mixture was diluted with ethyl acetate, washed with water, driedover sodium sulfate and concentrated. The residue was dissolved intetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.25 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added. After stirringfor 30 min, the reaction mixture was diluted with ethyl acetate, washedwith 1 M hydrochloric acid, dried over sodium sulfate and concentrated.The residue was purified by silica gel column chromatography to give thetitle compound as a colorless solid (0.47 g, 36%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3 Hz), 1.06-1.14 (3H, m),1.53-1.73 (4H, m), 1.94-2.06 (2H, m), 2.36 (2H, q, J=7.5 Hz), 2.68 (2H,t, J=7.3 Hz), 3.44-3.55 (2H, m), 3.81-3.91 (2H, m), 4.53-4.67 (1H, m),5.34 (2H, s), 6.97-7.05 (2H, m), 7.15-7.35 (6H, m), 7.49-7.75 (4H, m),12.40 (1H, s)

Example 549

-   6-ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]pyrimidin-4(3H)-one    potassium salt

6-Ethyl-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propyl-5-[4-(tetrahydro-2H-pyran-4-yloxy)phenyl]pyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (5 mL), and 8 M potassium hydroxidesolution (0.063 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.29 g, 90%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.3 Hz), 1.10 (3H, t, J=7.4Hz), 1.53-1.77 (4H, m), 1.93-2.06 (2H, m), 2.36 (2H, q, J=7.3 Hz), 2.71(2H, t, J=7.3 Hz), 3.44-3.55 (2H, m), 3.81-3.92 (2H, m), 4.54-4.67 (1H,m), 5.29 (2H, s), 7.00 (2H, d, J=8.7 Hz), 7.10-7.23 (4H, m), 7.25-7.55(6H, m)

Example 5505-(4-isopropoxyphenyl)-6-(methoxymethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

550a) 6-(methoxymethyl)-2-propylpyrimidin-4(3H)-one

A mixture of methyl 4-methoxy-3-oxobutanoate (15.0 g), butanimidamidehydrochloride (15 g) and sodium methoxide (28% in methanol, 51 mL) inmethanol (150 mL) was stirred overnight. The reaction mixture wasdiluted with ethyl acetate, washed with 1M hydrochloric acid, dried oversodium sulfate and concentrated. The residue was purified by silica gelcolumn chromatography to give the title compound as a pale yellow oil(17 g, 91%).

¹H NMR (300 MHz, CDCl₃) δ 1.00 (3H, t, J=7.4 Hz), 1.72-1.89 (2H, m),2.65 (2H, t, J=7.8 Hz), 3.48 (3H, s), 4.32 (2H, s), 6.45 (1H, s), 12.80(1H, br. s.)

550b)4′-{[4-(methoxymethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

A mixture of 6-(methoxymethyl)-2-propylpyrimidin-4(3H)-one (17 g),4′-(bromomethyl)biphenyl-2-carbonitrile (27 g) and potassium carbonate(25 g) in acetonitrile (300 mL) was stirred overnight at 50° C. Thereaction mixture was diluted with ethyl acetate, washed with 1 Mhydrochloric acid, dried over sodium sulfate and concentrated. Theresidue was purified by silica gel column chromatography to give thetitle compound as a pale yellow solid (15 g, 43%).

¹H NMR (300 MHz, CDCl₃) δ 0.97 (3H, t, J=7.4 Hz), 1.66-1.81 (2H, m),2.62-2.71 (2H, m), 3.50 (3H, s), 4.31 (2H, s), 5.37 (2H, s), 6.55 (1H,s), 7.29 (2H, d, J=8.3 Hz), 7.41-7.57 (4H, m), 7.60-7.79 (2H, m)

550c)4′-{[5-bromo-4-(methoxymethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile

To a solution of sodium acetate (3.4 g) and4′-{[4-(methoxymethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(15 g) in acetic acid (150 mL) was added bromine (2.1 mL), and themixture was stirred for 4 hr. Acetic acid was removed in vacuo, and thereaction mixture was diluted with ethyl acetate, washed with saturatedaqueous sodium hydrogen carbonate, dried over sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography to give the title compound as a pale yellow solid (7 g,39%).

¹H NMR (300 MHz, CDCl₃) δ 0.99 (3H, t, J=7.4 Hz), 1.70-1.87 (2H, m),2.70-2.78 (2H, m), 3.52 (3H, s), 4.54 (2H, s), 5.41 (2H, s), 7.31 (2H,d, J=8.0 Hz), 7.41-7.57 (4H, m), 7.61-7.78 (2H, m)

550d)5-(4-isopropoxyphenyl)-6-(methoxymethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of (4-isopropoxyphenyl)boronic acid (0.27 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.041 g) and4′-{[5-bromo-4-(methoxymethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.5 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate, passed through silica gel pad andconcentrated. The residue was dissolved in dimethyl sulfoxide (5 mL),and hydroxylamine hydrochloride (0.7 g) and sodium hydrogen carbonate (1g) were added. The mixture was stirred overnight at 90° C. Aftercooling, the reaction mixture was diluted with ethyl acetate, washedwith water, dried over sodium sulfate and concentrated. The residue wasdissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.24g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added. Afterstirring for 30 min, the reaction mixture was diluted with ethylacetate, washed with 1 M hydrochloric acid, dried over sodium sulfateand concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.35 g,56%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.4 Hz), 1.29 (6H, d, J=6.0Hz), 1.59-1.70 (2H, m), 2.65-2.75 (2H, m), 3.25 (3H, s), 4.07 (2H, s),4.59-4.72 (1H, m), 5.36 (2H, s), 6.91-6.98 (2H, m), 7.20-7.34 (6H, m),7.50-7.73 (4H, m) 12.39 (1H, s)

Example 551

5-(4-tert-butoxyphenyl)-6-(methoxymethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one

A mixture of (4-tert-butoxyphenyl)boronic acid (0.29 g),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.041 g) and4′-{[5-bromo-4-(methoxymethyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile(0.45 g) in 1,4-dioxane (10 mL) and 2 M cesium carbonate (2 mL) wasstirred overnight at 100° C. under an argon atmosphere. After cooling,the reaction mixture was diluted with ethyl acetate, washed with water,dried over sodium sulfate, passed through silica gel pad andconcentrated. The residue was dissolved in dimethyl sulfoxide (5 mL),and hydroxylamine hydrochloride (0.7 g) and sodium hydrogen carbonate (1g) were added. The mixture was stirred overnight at 90° C. Aftercooling, the reaction mixture was diluted with ethyl acetate, washedwith water, dried over sodium sulfate and concentrated. The residue wasdissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.24g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.22 mL) were added. Afterstirring for 30 min, the reaction mixture was diluted with ethylacetate, washed with 1 M hydrochloric acid, dried over sodium sulfateand concentrated. The residue was purified by silica gel columnchromatography to give the title compound as a colorless solid (0.52 g,81%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (3H, t, J=7.3 Hz), 1.34 (9H, s),1.57-1.73 (2H, m), 2.71 (2H, t, J=7.4 Hz), 3.23 (3H, s), 4.07 (2H, s),5.37 (2H, s), 6.98-7.04 (2H, m), 7.22-7.35 (6H, m), 7.50-7.74 (4H, m),12.39 (1H, s)

Example 552

5-(4-isopropoxyphenyl)-6-(methoxymethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-Isopropoxyphenyl)-6-(methoxymethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.3 g) was dissolved in ethanol (10 mL), and 8 M potassium hydroxidesolution (0.066 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.29 g, 91%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.4 Hz), 1.29 (6H, d, J=6.0Hz), 1.63-1.73 (2H, m), 2.72 (2H, t, J=7.3 Hz), 3.25 (3H, s), 4.07 (2H,s), 4.59-4.71 (1H, m), 5.32 (2H, s), 6.90-6.97 (2H, m), 7.13 (2H, d,J=8.3 Hz), 7.20-7.54 (8H, m)

Example 553

5-(4-tert-butoxyphenyl)-6-(methoxymethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-onepotassium salt

5-(4-tert-Butoxyphenyl)-6-(methoxymethyl)-3-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-2-propylpyrimidin-4(3H)-one(0.31 g) was dissolved in ethanol (10 mL), and 8 M potassium hydroxidesolution (0.066 mL) was added. The mixture was stirred for 1 hr. Ethanolwas removed in vacuo, diethyl ether was added, and the resulting solidwas collected by filtration to give the title compound as a colorlesssolid (0.31 g, 93%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (3H, t, J=7.3 Hz), 1.33 (9H, s),1.61-1.76 (2H, m), 2.73 (2H, t, J=7.4 Hz), 3.23 (3H, s), 4.06 (2H, s),5.32 (2H, s), 6.97-7.03 (2H, m), 7.13 (2H, d, J=8.3 Hz), 7.22-7.53 (8H,m)

Example 554

2-methyl-3-{4-[(4-methylcyclohexyl)oxy]phenyl}-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a mixture of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g), 4-methylcyclohexanol (0.29 mL), triphenylphosphine (0.60 g)and tetrahydrofuran (3.5 mL) was dropwise added diisopropylazodicarboxylate (1.9 M in toluene, 1.21 mL) at 60° C. The mixture wasstirred at 60° C. for 15 hr, and ethyl acetate and water were added tothe mixture. The layers were separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layer wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give the crudecompound. To a suspension of hydroxylamine hydrochloride (0.96 g) indimethyl sulfoxide (6 mL) was added sodium hydrogen carbonate (1.45 g)at 50° C. The mixture was stirred at 50° C. for 30 min, and the crudecompound obtained above was added. The mixture was stirred at 90° C. for20 hr and cooled to room temperature, and then ethyl acetate and waterwere added. The layers were separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layer wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. A mixture ofthe resulting residue, 1,1′-carbonyldiimidazole (0.22 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 ml) in tetrahydrofuran (6.0 ml)was stirred at room temperature for 3 hr. Ethyl acetate and 1 Mhydrochloric acid were added to the reaction mixture, and the layerswere separated. The aqueous layer was extracted with ethyl acetate. Thecombined organic layer was successively washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a white amorphous solid(0.31 g, 46%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.85-0.94 (m, 6H), 1.01-2.14 (m, 14H),2.47-2.54 (m, 2H), 3.86 (s, 2H), 4.58-4.66 (m, 1H), 6.99-7.73 (m, 12H),12.37 (s, 1H)

Example 555

3-[4-(cyclohexyloxy)phenyl]-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

To a mixture of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(0.50 g), cyclohexanol (0.24 mL), triphenylphosphine (0.60 g) andtetrahydrofuran (3.5 mL) was dropwise added diisopropyl azodicarboxylate(1.9 M in toluene, 1.2 mL) at 60° C. The mixture was stirred at 60° C.for 15 hr, and ethyl acetate and water were added to the mixture. Thelayers were separated, and the aqueous layer was extracted with ethylacetate. The combined organic layer was successively washed with waterand saturated brine, dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography to give the crude compound. To a suspension ofhydroxylamine hydrochloride (0.96 g) in dimethyl sulfoxide (6 mL) wasadded sodium hydrogen carbonate (1.45 g) at 50° C. The mixture wasstirred at 50° C. for 30 min, and the crude compound obtained above wasadded. The mixture was stirred at 90° C. for 20 hr and cooled to roomtemperature, and then ethyl acetate and water were added. The layerswere separated, and the aqueous layer was extracted with ethyl acetate.The combined organic layer was successively washed with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedunder reduced pressure. A mixture of the resulting residue,1,1′-carbonylidimidazole (0.22 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene(0.21 ml) in tetrahydrofuran (6.0 ml) was stirred at room temperaturefor 3 hr. Ethyl acetate and 1 M hydrochloric acid were added to thereaction mixture and the layers were separated. The aqueous layer wasextracted with ethyl acetate. The combined organic layer wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give the titlecompound as a white amorphous solid (0.29 g, 44%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.4 Hz, 3H), 1.22-2.01 (m, 12H),2.06 (s, 3H), 2.46-2.53 (m, 2H), 3.86 (s, 2H), 4.33-4.48 (m, 1H),7.00-7.74 (m, 12H), 12.37 (s, 1H)

Example 556

2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propyl-3-(4-{[4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]oxy}phenyl)pyrimidin-4(3H)-one

To a mixture of4′-{[1-(4-hydroxyphenyl)-2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(1.0 g), 4-(tetrahydro-2H-pyran-2-yloxy)cyclohexanol (0.69 g),triphenylphosphine (0.90 g) and tetrahydrofuran (4.6 mL) was dropwiseadded diisopropyl azodicarboxylate (1.9 M in toluene, 1.8 mL) at 60° C.The mixture was stirred at 50° C. for 3 hr, and ethyl acetate and waterwere added to the mixture. The layers were separated, and the aqueouslayer was extracted with ethyl acetate. The combined organic layer wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. The residuewas purified by silica gel column chromatography to give the crudecompound. To a suspension of hydroxylamine hydrochloride (1.60 g) indimethyl sulfoxide (12 mL) was added sodium hydrogen carbonate (2.3 g)at 50° C. The mixture was stirred at 50° C. for 30 min, and the crudecompound obtained above was added. The mixture was stirred at 90° C. for15 hr and cooled to room temperature, and then ethyl acetate and waterwere added. The layers were separated, and the aqueous layer wasextracted with ethyl acetate. The combined organic layer wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated under reduced pressure. A mixture ofthe resulting residue, 1,1′-carbonyldiimidazole (0.45 g) and1,8-diazabicyclo[5.4.0]undec-7-ene (0.42 ml) in tetrahydrofuran (10 ml)was stirred at room temperature for 2 hr. Ethyl acetate and 1Mhydrochloric acid were added to the reaction mixture, and the layerswere separated. The aqueous layer was extracted with ethyl acetate. Thecombined organic layer was successively washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography to give the title compound as a white amorphous solid(0.29 g, 50%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.89 (t, J=7.3 Hz, 3H), 1.35-2.11 (m, 18H),2.46-2.56 (m, 2H), 3.37-3.92 (m, 5H), 4.37-4.55 (m, 1H), 4.66-4.73 (m,1H), 7.01-7.72 (m, 12H), 12.38 (s, 1H)

Example 5573-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

557a) 4-oxocyclohexyl benzoate

A mixture of 1,4-dioxaspiro[4.5]decan-8-ol (4.44 g), benzoyl chloride(3.9 mL), pyridine (2.7 mL) and tetrahydrofuran (50 mL) was stirred atroom temperature for 12 hr. The reaction mixture was diluted with ethylacetate, and washed with saturated aqueous sodium hydrogen carbonate andsaturated brine, dried over anhydrous magnesium sulfate and concentratedin vacuo. The residue was dissolved in tetrahydrofuran (50 mL), and 6 Mhydrochloric acid (4.7 mL) was added thereto, and then the mixture wasstirred at 60° C. for 12 hr. The reaction mixture was diluted with ethylacetate, and the organic layer was separated. The aqueous layer wasextracted with ethyl acetate, and the combined organic layer wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to give the title compound as a paleyellow oil (2.64 g, 43%).

¹H NMR (300 MHz, CDCl₃) δ 2.10-2.34 (m, 4H) 2.38-2.51 (m, 2H), 2.59-2.73(m, 2H), 5.40-5.48 (m, 1H), 7.41-7.51 (m, 2H), 7.54-7.63 (m, 1H),8.02-8.12 (m, 2H)

557b) 4,4-difluorocyclohexyl benzoate

To a solution of 4-oxocyclohexyl benzoate (2.64 g) in toluene (40 ml)was added dropwise diethylaminosulfur trifluoride (2.4 mL) at 0° C. overa period of 5 min, and the mixture was stirred at room temperature for12 hr. The reaction mixture was concentrated in vacuo, and the residuewas diluted with ethyl acetate. The mixture was washed with water andsaturated brine, dried over anhydrous magnesium sulfate and concentratedin vacuo. The residue was purified by column chromatography on silicagel to give the title compound as a pale yellow oil (2.0 g, 69%).

¹H NMR (300 MHz, CDCl₃) δ 1.69-2.41 (m, 8H) 4.97-5.36 (m, 1H) 7.40-7.50(m, 2H) 7.52-7.62 (m, 1H) 8.00-8.07 (m, 2H)

557c) 4,4-difluorocyclohexanol

A mixture of 4,4-difluorocyclohexyl benzoate (2.0 g), 1M sodiumhydroxide solution (10 mL) and ethanol (20 mL) was stirred at 70° C. for3 hr. The reaction mixture was added to a mixture of ethyl acetate andwater, and the organic layer was separated. The aqueous layer wasextracted with ethyl acetate, and the combined organic layer wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to give the title compound (1.0 g,90%).

¹H NMR (300 MHz, CDCl₃) δ 1.56-2.22 (m, 8H) 3.85-4.05 (m, 2H)

557d)4′-[(1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile

A mixture of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(600 mg), 4,4-difluorocyclohexanol (362 mg,), diisopropylazodicarboxylate (1.9 M in toluene, 1.4 mL), triphenylphosphine (698 mg)and tetrahydrofuran (10 ml) was stirred at 60° C. for 3 hr. The reactionmixture was diluted with ethyl acetate, and successively washed withwater and saturated brine, dried over anhydrous magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel to give the title compound as a pale yellow oil (635 mg,86%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7. Hz, 3H) 1.15 (t, J=7.44 Hz, 3H)1.62-2.26 (m, 12H) 2.63-2.73 (m, 2H) 3.96 (s, 2H) 4.49-4.60 (m, 1H)6.98-7.06 (m, 2H) 7.11-7.17 (m, 2H) 7.37-7.51 (m, 6H) 7.58-7.66 (m, 1H)7.74 (dd, J=7.72, 0.94 Hz, 1H)

557e)3-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A suspension of hydroxylamine hydrochloride (661 mg) and sodium hydrogencarbonate (941 mg) in dimethyl sulfoxide (5 mL) was stirred at 40° C.for 30 min, and then4′-[(1-{4-[(4,4-difluorocyclohexyl)oxy]phenyl}-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile(635 mg) was added to the mixture, and the mixture was stirred at 90° C.for 12 hr. Water was added to the reaction mixture, and the precipitatedsolid was collected by filtration. The obtained solid was dissolved inethyl acetate. The solution was washed with saturated brine and driedover anhydrous sodium sulfate, and the solvent was evaporated. Theresidue was dissolved in tetrahydrofuran (20 mL), and then1,1′-carbonyldiimidazole (272 mg) and 1,8-diazabicyclo[5,4,0]undec-7-ene(0.25 mL) were added thereto. The mixture was stirred at roomtemperature for 2 hr. The reaction mixture was diluted with ethylacetate, and the mixture was successively washed with water andsaturated brine (20 mL), dried over anhydrous magnesium sulfate andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel to give the title compound as a pale yellow amorphoussolid (12.1 mg, 2%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.90 (t, J=7.25 Hz, 3H) 1.17 (t, J=7.16 Hz,3H) 1.51-1.67 (m, 2H) 1.73-2.15 (m, 6H) 2.22-2.36 (m, 2H) 2.49-2.59 (m,2H) 3.87 (s, 2H) 4.03 (q, J=7.16 Hz, 2H) 4.61-4.73 (m, 1H) 7.08-7.15 (m,2H) 7.19-7.33 (m, 6H) 7.46-7.59 (m, 2H) 7.62-7.73 (m, 2H) 12.17-12.51(m, 1H)

Example 5583-[4-(1,4-dioxaspiro[4.5]dec-8-yloxy)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

558a) 1,4-dioxaspiro[4.5]decan-8-ol

To a solution of 1,4-dioxaspiro[4.5]decan-8-one (10.0 g) in methanol(120 ml) was added sodium borohydride (4.84 g) at 0° C. over a period of15 min, and the mixture was stirred at room temperature for 3 hr. Thereaction mixture was concentrated in vacuo, and the residue was dilutedwith ethyl acetate. The mixture was washed with water and saturatedbrine, dried over anhydrous magnesium sulfate and concentrated in vacuo.The residue was purified by column chromatography on silica gel to givethe title compound as a pale yellow oil (6.24 g, 62%).

¹H NMR (300 MHz, CDCl₃) δ 1.30 (d, J=4.52 Hz, 1H) 1.53-1.72 (m, 4H)1.77-1.94 (m, 4H) 3.75-3.86 (m, 1H) 3.93-3.97 (m, 4H)

558b)4′-({1-[4-(1,4-dioxaspiro[4.5]dec-8-yloxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile

A mixture of4′-{[2-ethyl-1-(4-hydroxyphenyl)-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile(4.0 g), 1,4-dioxaspiro[4.5]decan-8-ol (2.82 g), diisopropylazodicarboxylate (1.9 M in toluene, 3.2 mL), triphenylphosphine (4.67 g)and tetrahydrofuran (20 ml) was stirred at room temperature for 2 hr.The reaction mixture was diluted with ethyl acetate, successively washedwith water and saturated brine, dried over anhydrous magnesium sulfateand concentrated in vacuo. The residue was purified by columnchromatography on silica gel to give the title compound as a pale yellowamorphous solid (5.13 g, 98%).

¹H NMR (300 MHz, CDCl₃) δ 1.01 (t, J=7.35 Hz, 3H) 1.14 (t, J=7.44 Hz,3H) 1.56-1.79 (m, 4H) 1.84-2.04 (m, 6H) 2.38 (q, J=7.41 Hz, 2H)2.62-2.72 (m, 2H) 3.89-4.05 (m, 6H) 4.38-4.49 (m, 1H) 6.98-7.05 (m, 2H)7.07-7.14 (m, 2H) 7.35-7.52 (m, 6H) 7.55-7.66 (m, 1H) 7.74 (dd, J=7.72,0.94 Hz, 1H)

558c)3-[4-(1,4-dioxaspiro[4.5]dec-8-yloxy)phenyl]-2-ethyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one

A suspension of hydroxylamine hydrochloride (5.14 g) and sodium hydrogencarbonate (7.31 g) in dimethyl sulfoxide (30 mL) was stirred at 40° C.for 30 min, and then4′-({1-[4-(1,4-dioxaspiro[4.5]dec-8-yloxy)phenyl]-2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile(5.13 g) was added to the mixture, and the mixture was stirred at 90° C.for 12 hr. Water was added to the reaction mixture, and the precipitatedsolid was collected by filtration. The obtained solid was dissolved inethyl acetate. The solution was washed with saturated brine and driedover anhydrous sodium sulfate, and the solvent was evaporated. Theresidue was dissolved in tetrahydrofuran (40 mL), and then1,1′-carbonyldiimidazole (2.12 g, 13.1 mmol) and1,8-diazabicyclo[5,4,0]undec-7-ene (2.0 mL, 13.1 mmol) were addedthereto. The mixture was stirred at room temperature for 2 hr. Thereaction mixture was diluted with ethyl acetate, and the mixture wassuccessively washed with water and saturated brine, dried over anhydrousmagnesium sulfate and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel to give the title compound as a paleyellow amorphous solid (3.63 g, 64%).

¹H NMR (300 MHz, DMSO-d₆) δ 0.92 (t, J=7.35 Hz, 3H) 1.05 (t, J=6.88 Hz,3H) 1.48-2.00 (m, 12H) 2.28 (q, J=7.41 Hz, 2H) 2.52-2.58 (m, 2H)3.80-3.86 (m, 2H) 3.88 (s, 2H) 4.49-4.60 (m, 1H) 6.98-7.12 (m, 4H)7.18-7.29 (m, 3H) 7.37-7.49 (m, 2H) 7.52-7.68 (m, 3H) 12.47 (s, 1H)

Experimental Example 1 Binding Assay Using Human AT1 Receptor-ExpressingCHO-K1 Cell Membrane Fraction

The membrane fraction for human AT1 receptor binding assay was preparedas follows. CHO-K1 cell capable of stable expression of human AT1receptor was cultured, recovered, suspended in homogenize buffer (10 mMNaHCO₃ (pH 7.4), 5 mM EDTA, 1×Complete EDTA free) [manufactured byRoche, Switzerland], and homogenized. The homogenate was centrifuged atlow-speed (900×g, 10 min, 4° C.), and the supernatant was recovered andultracentrifuged (90,000×g, 1 hr, 4° C.). The supernatant was discarded,and the pellets were resuspended in resuspension buffer (50 mM Tris (pH7.4), 1 mM EDTA, 1×Complete EDTA free).

The binding assay was performed in the presence of 22.5 pM[¹²⁵I]-angiotensin II [manufactured by PerkinElmer, USA], 9 μg of AT1membrane and test compound in 100 μL (total reaction volume) of reactionbuffer (50 mM Tris (pH 7.4), 10 mM MgCl₂ supplemented or notsupplemented with 0.3 mg/mL fatty acid-free bovine serum albumin[manufactured by Wako Pure Chemical Industries, Ltd., Japan]). Thereaction mixture was incubated in 96 well polypropylene plate for 1 hrat room temperature, and the reaction was quenched by rapid filtration(96 well cell harvester) through a GF/C filter treated with wash buffer(50 mM Tris (pH 7.4)). Subsequently, the filter was washed 5 times with0.3 mL of ice-cooled wash buffer. The filter was air-dried, and[¹²⁵I]-angiotensin II binding radioactivity was assayed with Top Countscintillation counter. Total binding was measured in the presence of 1%DMSO and nonspecific binding was measured in the presence of 1 μMCV-11974. The binding data was analyzed by GraphPad Prism program andthe IC₅₀ value (compound concentration showing 50% of the maximum valueof inhibition percent) of the test compound was calculated. The resultsare shown in Tables 1 to 5.

Experimental Example 2 Evaluation of PPARγ Activating Action

PPARγ:RXRα:4ERPP/CHO-K1 cells obtained in the following ReferenceExample 5 were cultured in F12 medium [manufactured by INVITROGEN, USA]containing 10% fetal bovine serum [manufactured by MOREGATE, Australia],seeded in a 96-well half area white plate [manufactured by CorningCoster Corporation, USA] at the density of 5×10³ cells/well and culturedin a CO₂ gas incubator at 37° C. overnight.

Then the medium was removed from the 96-well half area white plate, 45μl of Ham's F12 medium containing 0.1% fatty acid-free bovine serumalbumin (BSA) and 5 μl of test compound were added, and the cells werecultured in a CO₂ gas incubator at 37° C. for 1 day. The medium wasremoved and 20 μl of PicaGene 7.5 [manufactured by TOYO INK MFG. CO.,LTD., Japan] diluted 2-fold with HBSS (HANKS' BALANCED SALT SOLUTION)[manufactured by BIO WHITTAKER, USA] was added. After stirring, theluciferase activity was determined using 1420 ARVO Multilabel Counter[manufactured by PerkinElmer, USA].

The percent (%) was calculated from the luciferase activity of each testcompound when the luciferase activity of the control compound (compoundX:5-[3-(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxyphenyl)propyl]-1,3-oxazolidine-2,4-dione)(1 μM) was 100% and that of the test compound non-administration groupwas 0%. The results are shown in Tables 1 to 5.

TABLE 1 Example AT₁ receptor binding PPARγ activating action No.inhibitory action (IC₅₀ (nM)) (activation % (10^(−6 M))) 3 2.5 57.1 41.9 35.8 7 1.4 42.6 28 1.6 16.2 32 1.3 55.6 37 1.3 29.8 42 1.5 61.2 471.4 61.2 48 1.8 68.8 50 1.7 34.3 51 1.5 19.6 58 1.5 55.1 64 2.0 59.9 672.0 49.4 71 1.8 46.3 81 1.6 62.9 88 1.7 31.2 94 1.8 41.5 103 1.5 50.2105 1.9 64.1 107 2.0 60.0 108 2.2 31.7 112 1.7 52.1 118 1.8 50.2 128 1.924.3 131 2.2 34.2 136 2.9 32.9 141 1.8 38.3 142 1.7 32.8 144 1.5 22.7145 1.8 36.5

TABLE 2 Example AT₁ receptor binding PPARγ activating action No.inhibitory action (IC₅₀ (nM)) (activation % (10^(−6 M))) 152 2.1 64.8160 1.8 61.6 165 1.7 59.0 178 2.6 37.5 202 1.5 25.3 204 1.6 27.4 206 2.021.8 217 1.1 26.8 222 1.3 29.3 234 1.2 33.9 235 1.5 27.6 239 1.8 31.6249 1.6 30.5 255 1.7 30.5 256 2.0 45.7 265 1.7 27.8 271 1.9 37.1 275 1.817.0 277 1.8 33.5 287 1.8 40.9 293 1.8 28.2 294 1.8 47.1 309 1.6 31.5310 1.9 27.1 311 1.6 38.1 312 1.6 50.3 313 1.5 31.0 318 1.8 19.2 319 1.817.2 323 2.1 20.0 324 1.7 45.2

TABLE 3 Example AT₁ receptor binding PPARγ activating action No.inhibitory action (IC₅₀ (nM)) (activation % (10^(−6 M))) 325 3.4 30.2327 2.2 22.6 338 1.8 32.5 343 0.7 15.2 346 1.0 21.8 356 1.1 16.6 362 2.458.7 363 2.1 53.7 364 1.9 32.6 365 1.8 25.3 368 2.0 50.2 369 1.9 36.3373 2.4 48.4 376 1.7 22.0 377 1.5 30.3 378 1.5 46.9 379 3.4 31.0 381 1.228.2 382 1.2 27.2 388 1.6 34.4 389 1.8 18.1 390 1.2 19.9 395 1.7 16.0396 2.2 50.6 397 2.1 48.6 400 2.8 21.3 401 1.5 25.3 402 1.8 24.1 406 1.541.9 408 1.4 48.7 410 2.1 19.5

TABLE 4 Example AT₁ receptor binding PPARγ activating action No.inhibitory action (IC₅₀ (nM)) (activation % (10^(−6 M))) 413 1.7 18.9414 1.1 45.0 415 1.0 49.7 416 1.2 53.5 417 1.6 33.7 419 1.3 27.2 422 0.922.2 424 1.3 33.5 425 1.2 37.5 427 1.4 17.7 437 1.0 18.1 439 1.4 20.1440 1.6 29.9 444 1.3 55.4 445 1.2 62.9 450 1.8 23.7 452 2.1 52.9 453 2.922.5 455 2.0 16.0 456 1.8 30.0 457 3.5 36.0 458 2.2 36.0 459 2.1 40.0460 2.2 30.0 467 2.5 35.7 473 3.6 15.7 475 2.0 28.7 476 2.1 18.5 480 3.230.8 482 1.9 30.4 483 2.4 31.5

TABLE 5 Example AT₁ receptor binding PPARγ activating action No.inhibitory action (IC₅₀ (nM)) (activation % (10^(−6 M))) 484 2.3 19.4485 2.0 23.5 488 1.9 16.7 500 2.7 35.9 501 2.6 31.8 507 2.2 32.4 509 1.216.2 510 2.3 24.4 511 1.3 31.0 512 1.3 20.3

In the above-mentioned Tables, the compounds of Examples 309, 310, 311,312, 313, 473, 476 and 488 are potassium salts and other Examplecompounds are free forms.

Reference Example 1 Cloning of Human PPARγ Gene

Human PPARγ gene was cloned by a PCR method using heart cDNA[manufactured by Toyobo Co., Ltd., QUICK-Clone cDNA] as a template, anda primer set shown below which was prepared by reference to the basesequence of PPARγ gene reported by Greene et al. [Gene Expr., 1995, vol.4(4-5), pp. 281-299].

PAG-U: (SEQ ID NO: 1) 5′-GTG GGT ACC GAA ATG ACC ATG GTT GAC ACA GAG-3′PAG-L: (SEQ ID NO: 2) 5′-GGG GTC GAC CAG GAC TCT CTG CTA GTA CAA GTC-3′

The PCR reaction was performed by Hot Start method using AmpliWax PCRGem 100 [manufactured by Takara Shuzo Co., Ltd., Japan]. First, 2 μl of10×LA PCR Buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl each of 12.5 μMprimer solutions and 10 μl of sterile distilled water were mixed toobtain a bottom layer solution mixture. One μl of human heart cDNA (1ng/ml) as a template, 3 μl of 10×LA PCR Buffer, 1 μl of 2.5 mM dNTPsolution, 0.5 μl of TaKaRa LA Taq DNA polymerase [manufactured by TakaraShuzo Co., Ltd., Japan] and 24.5 μl of sterile distilled water weremixed to obtain a top layer solution mixture.

To the bottom layer solution mixture described above was added one unitof AmpliWax PCR Gem 100 [manufactured by Takara Shuzo Co., Ltd., Japan],which was treated at 70° C. for 5 minutes and then in ice for 5 minutes.Then, the top layer solution mixture was added to the mixture to preparethe reaction mixture for PCR. A tube containing the reaction mixture wasset on a thermal cycler [manufactured by PerkinElmer, USA] and treatedat 95° C. for 2 minutes. Furthermore, after repeating the cycle of 95°C. for 15 seconds and 68° C. for 2 minutes 35 times, the tube wastreated at 72° C. for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 1.4 kb DNA fragment containing PPARγ gene wasrecovered from the gel, and then inserted into pT7 Blue-T vector[manufactured by Takara Shuzo Co., Ltd., Japan] to obtain plasmidpTBT-hPPARγ.

Reference Example 2 Cloning of Human RXRα Gene

A human RXRα gene was cloned by a PCR method using kidney cDNA[manufactured by Toyobo Co., Ltd., QUICK-Clone cDNA] as a template, anda primer set shown below which was prepared with reference to the basesequence of RXRα gene reported by Mangelsdorf, D. J. et al. (Nature,1990, vol. 345 (6272), pp. 224-229).

XRA-U: (SEQ ID NO: 3) 5′-TTA GAA TTC GAC ATG GAC ACC AAA CAT TTC CTG-3′XRA-L: (SEQ ID NO: 4) 5′-CCC CTC GAG CTA AGT CAT TTG GTG CGG CGC CTC-3′

The PCR reaction was performed by Hot Start method using AmpliWax PCRGem 100 [manufactured by Takara Shuzo Co., Ltd., Japan]. First, 2 μl of10×LA PCR Buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl each of 12.5 μMprimer solutions and 10 μl of sterile distilled water were mixed toobtain a bottom layer solution mixture. One μl of human kidney cDNA (1ng/ml) as a template, 3 μl of 10×LA PCR Buffer, 1 μl of 2.5 mM dNTPsolution, 0.5 μl of TaKaRa LA Taq DNA polymerase [manufactured by TakaraShuzo Co., Ltd., Japan] and 24.5 μl of sterile distilled water weremixed to obtain a top layer solution mixture.

To the bottom layer solution mixture described above was added one unitof AmpliWax PCR Gem 100 [manufactured by Takara Shuzo Co., Ltd., Japan],which was treated at 70° C. for 5 minutes and then in ice for 5 minutes.Then, the top layer solution mixture was added to the mixture to preparethe reaction mixture for PCR. A tube containing the reaction mixture wasset on a thermal cycler [manufactured by PerkinElmer, USA] and treatedat 95° C. for 2 minutes. Furthermore, after repeating the cycle of 95°C. for 15 seconds and 68° C. for 2 minutes 35 times, the tube wastreated at 72° C. for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 1.4 kb DNA fragment containing RXRα gene wasrecovered from the gel, and then inserted into pT7 Blue-T vector[manufactured by Takara Shuzo Co., Ltd., Japan] to obtain plasmidpTBT-hRXRα.

Reference Example 3 Construction of Reporter Plasmid

A DNA fragment containing PPAR-response element (PPRE) of an acyl CoAoxidase was prepared using the following 5′-terminal phosphorylatedsynthetic DNA.

PPRE-U: (SEQ ID NO: 5) 5′-pTCGACAGGGGACCAGGACAAAGGTCACGTTCGGGAG-3′PPRE-L: (SEQ ID NO: 6) 5′-pTCGACTCCCGAACGTGACCTTTGTCCTGGTCCCCTG-3′

First, PPRE-U and PPRE-L were annealed and inserted to SalI site ofplasmid pBlueScript SK+. By determining the base sequence of theinserted fragment, plasmid pBSS-PPRE4, in which 4 PPREs were ligated intandem, was selected.

An HSV thymidine kinase minimum promoter (TK promoter) region was clonedby a PCR method using pRL-TK vector [manufactured by Promega, USA] as atemplate, and a primer set shown below which was prepared with referenceto the base sequence of the promoter region of thymidine kinase genereported by Luckow, B et al. (Nucleic Acids Res., 1987, vol. 15(13), p.5490)

(SEQ ID NO: 7) TK-U: 5′-CCCAGATCTCCCCAGCGTCTTGTCATTG-3′ (SEQ ID NO: 8)TK-L: 5′-TCACCATGGTCAAGCTTTTAAGCGGGTC-3′

The PCR reaction was performed by Hot Start method using AmpliWax PCRGem 100 [manufactured by Takara Shuzo Co., Ltd., Japan]. First, 2 μl of10×LA PCR Buffer, 3 μl of 2.5 mM dNTP solution, 2.5 μl each of 12.5 μMprimer solutions and 10 μl of sterile distilled water were mixed toobtain a bottom layer solution mixture. One μl of pRL-TK vector[manufactured by Promega, USA] as a template, 3 μl of 10×LA PCR Buffer,1 μl of 2.5 mM dNTP solution, 0.5 μl of TaKaRa LA Taq DNA polymerase[manufactured by Takara Shuzo Co., Ltd., Japan] and 24.5 μl of steriledistilled water were mixed to obtain a top layer solution mixture.

To the bottom layer solution mixture described above was added one unitof AmpliWax PCR Gem 100 [manufactured by Takara Shuzo Co., Ltd., Japan],which was treated at 70° C. for 5 minutes and then in ice for 5 minutes.Then, the top layer solution mixture was added to the mixture to preparethe reaction mixture for PCR. A tube containing the reaction mixture wasset on a thermal cycler [manufactured by PerkinElmer, USA] and treatedat 95° C. for 2 minutes. Furthermore, after repeating the cycle of 95°C. for 15 seconds and 68° C. for 2 minutes 35 times, the tube wastreated at 72° C. for 8 minutes.

The PCR product thus obtained was subjected to electrophoresis onagarose gel (1%), and 140 bp DNA fragment containing TK promoter wasrecovered from the gel, and then inserted into pT7 Blue-T vector[manufactured by Takara Shuzo Co., Ltd., Japan]. By digesting theplasmid thus obtained with the restriction enzymes Bg1II and NcoI, afragment containing TK promoter was obtained, which was ligated to theBg1II-NcoI fragment of plasmid pGL3-Basic vector [manufactured byPromega, USA] to obtain plasmid pGL3-TK.

A 4.9 kb NheI-XhoI fragment of plasmid pGL3-TK thus obtained was ligatedto a 200 bp NheI-XhoI fragment of plasmid pBSS-PPRE4 to obtain plasmidpGL3-4ERPP-TK.

This plasmid pGL3-4ERPP-TK was digested with BamHI [manufactured byTakara Shuzo Co., Ltd., Japan], and then treated with T4DNA polymerase[manufactured by Takara Shuzo Co., Ltd., Japan] to form a blunt-end,whereby obtaining a DNA fragment.

On the other hand, pGFP-C1 [manufactured by Toyobo Co., Ltd., Japan] wasdigested with Bsu36I (manufactured by NEB, UK], and then treated withT4DNA polymerase [manufactured by Takara Shuzo Co., Ltd., Japan] to forma blunt-end whereby obtaining a 1.6 kb DNA fragment.

The both DNA fragments were ligated to construct a reporter plasmidpGL3-4ERPP-TK neo.

Reference Example 4 Construction of Expression Plasmid for Human PPARγand RXRα)

A 7.8 kb FspI-NotI fragment of plasmid pVgRXR [manufactured byInvitrogen, USA] was ligated to a 0.9 kb FspI-NotI fragment containingRXRα gene of plasmid pTBT-hRXRα obtained in Reference Example 2 toprepare plasmid pVgRXR2. Then, pVgRXR2 was digested with BstXI, and thentreated with T4DNA polymerase [manufactured by Takara Shuzo Co., Ltd.,Japan] to give a blunt-ended product. Then digestion with KpnI gave a6.5 kb DNA fragment.

On the other hand, plasmid pTBT-hPPARγ obtained in Reference Example 1was digested with SalI, and then treated with T4DNA polymerase[manufactured by Takara Shuzo Co., Ltd., Japan] to give a blunt-endedproduct. Then digestion with KpnI gave a 1.4 kb DNA fragment containinghuman PPARγ gene.

The both DNA fragments were ligated to construct plasmid pVgRXR2-hPPARγ.

Reference Example 5 Introduction of Human PPARγ- and RXRα-ExpressionPlasmid and Reporter Plasmid into CHO-K1 Cell as Well as Establishmentof Expressed Cell

A CHO-K1 cell cultured in a 150 cm² cell culture flask [manufactured byCorning Costar Corporation, USA] containing Ham's F12 medium[manufactured by INVITROGEN, USA] supplemented with 10% fetal bovineserum [manufactured by INVITROGEN, USA] was scraped by treating with 0.5g/L trypsin-0.2 g/L EDTA (ethylenediaminetetraacetic acid) [manufacturedby Life Technologies, Inc., USA], and then the cell was washed with PBS(Phosphate-buffered saline) [manufactured by INVITROGEN, USA],centrifuged (1000 rpm, 5 minutes) and suspended in PBS. Subsequently,DNA was introduced into the cell under the conditions shown below usingGENE PULSER [manufactured by Bio-Rad Laboratories, USA].

Namely, to a cuvette having a 0.4 cm gap were added 8×10⁶ cells and 10μg of plasmid pVgRXR2-hPPARγ obtained in Reference Example 4 and 10 μgof reporter plasmid pGL3-4ERPP-TK neo obtained in Reference Example 3,which was subjected to electroporation at the voltage of 0.25 kV underthe capacitance of 960 μF. Subsequently, the cell was transferred into aF12 medium containing 10% fetal bovine serum and cultured for 24 hours,and then the cell was scraped again and centrifuged, and then suspendedin Ham's F12 medium containing 10% fetal bovine serum supplemented with500 μg/ml of Geneticin [manufactured by INVITROGEN, USA] and 250 μg/mlof Zeocin [manufactured by INVITROGEN, USA]. The obtained suspension wasdiluted to the density of 1 cells/ml and inoculated in a 96-well plate[manufactured by Corning Costar Corporation, USA], which was cultured ina CO₂ gas incubator at 37° C., whereby obtaining a Geneticin- andZeocin-resistant transformant.

Subsequently, after the transformant cell line thus obtained wascultured in a 24-well plate [manufactured by Corning Costar Corporation,USA], a cell line in which the luciferase was expressed and induced,i.e., PPARγ:RXRα:4ERPP/CHO-K1 cell was selected by the addition of 10 μMpioglitazone hydrochloride.

Formulation Examples

When compound (I) of the present invention is to be used, for example,as an agent for the prophylaxis or treatment of cardiovascular diseases,metabolic diseases, and/or central nervous system diseases, it can beused, for example, according to the following formulations. For example,using a compound of Example 7, 47, 88, 165 or 239 as compound (I),preparations having the following formulations can be produced.

Formulation Example 1 (capsule) (1) compound (I) 10 mg (2) lactose 90 mg(3) microcrystalline cellulose 70 mg (4) magnesium stearate 10 mg 1capsule 180 mg 

(1), (2), (3) and ½ of (4) are blended and granulated. The rest of (4)is added and the whole is encapsulated in a gelatin capsule.

Formulation Example 2 (tablet) (1) compound (I) 10 mg (2) lactose 35 mg(3) cornstarch 150 mg  (4) microcrystalline cellulose 30 mg (5)magnesium stearate  5 mg 1 tablet 230 mg 

(1), (2), (3), ⅔ of (4) and ½ of (5) are blended and granulated. Therest of (4) and (5) are added to the granules and the mixture iscompression molded to give tablet.

Formulation Example 3 (injection) (1) compound (I)  10 mg (2) inositol100 mg (3) benzyl alcohol  20 mg 1 ampoule 130 mg

(1), (2) and (3) are dissolved in distilled water for injection to thetotal amount of 2 mL and filled in an ampoule. All steps are performedunder aseptic conditions.

INDUSTRIAL APPLICABILITY

The compound of the present invention has an angiotensin II receptorantagonistic action and a peroxisome proliferator-activated receptor(PPAR) agonistic action, and is useful as a pharmaceutical agent such asan agent for the prophylaxis or treatment of cardiovascular diseasessuch as hypertension, cardiac diseases (cardiac hypertrophy, cardiacfailure, myocardial infarction and the like), arteriosclerosis, kidneydiseases (diabetic nephropathy, chronic glomerulonephritis and thelike), stroke and the like; metabolic diseases such as hyperlipidemia,obesity, diabetes and the like; and/or central nervous system diseasessuch as depression, dementia, Alzheimer's disease and the like, and thelike.

1.3-(2,2-Dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.
 2. A crystalline compound of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.
 3. A crystalline compound of hydrate of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.
 4. A crystalline compound of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,which has an X-ray powder diffraction analysis pattern with peaks atdiffraction angle: 2θ(°) of 4.76, 6.10, 7.30, 7.86, 8.16, 9.18, 9.60,10.66, 11.28, 11.94, 12.58, 13.34, 14.62, 15.10, 15.46, 16.34, 16.90,17.76, 18.64, 19.34, 20.86, 21.58, 22.42, 24.36, 24.86.
 5. A crystallinecompound of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-one,which has an X-ray powder diffraction analysis pattern with peaks atdiffraction angle: 2θ(°) of 4.38, 7.42, 8.90, 9.68, 10.92, 11.24, 11.90,12.56, 12.88, 13.34, 14.06, 14.92, 16.64, 17.30, 17.80, 18.70, 19.08,19.40, 20.36, 20.90, 21.20, 21.50, 21.98, 22.40, 22.72, 22.98, 23.68. 6.A crystalline compound of hydrate of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt, which has an X-ray powder diffraction analysis patternwith peaks at diffraction angle: 2θ(°) of 5.02, 5.36, 9.46, 10.66,11.80, 13.42, 17.06, 17.78, 19.00, 19.18, 20.18, 20.88, 21.38, 23.26,23.78, 25.06, 25.74, 26.06, 26.90, 27.34.
 7. A crystalline compound of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt.
 8. A crystalline compound of a hydrate of3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-onepotassium salt.
 9. The compound according to claim 1 which is a hydrateof3-(2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-2-methyl-5-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-6-propylpyrimidin-4(3H)-oneor a salt thereof.